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Sahu VK, Sur S, Agarwal S, Madhyastha H, Ranjan A, Basu S. Unveiling theranostic potential: Insights into cell-free microRNA-protein interactions. Biophys Chem 2025; 322:107421. [PMID: 40048894 DOI: 10.1016/j.bpc.2025.107421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 09/02/2024] [Accepted: 03/01/2025] [Indexed: 04/27/2025]
Abstract
MicroRNAs (miRNAs) belong to a short endogenous class of non-coding RNAs which have been well studied for their crucial role in regulating cellular homeostasis. Their role in the modulation of diverse biological pathways by interacting with cellular proteins, genes, and RNAs through cellular communication projects them as promising biomarkers and therapeutic targets. However, studying miRNA-protein interactions specific to disease in the extracellular or cell-free environments for drug discovery and biomarker establishment is challenging and resource-intensive due to their structural complexities. In this study, we present a computational approach to uncover patterns in miRNA-protein interactions in the cell-free milieu leveraging existing experimental data. We employed motif discovery tools, extracted motifs from 3D protein and miRNA structures, and conducted molecular docking analyses to identify and rank these interactions. This in silico-based approach reveals 204 and 2874 consensus sequences in miRNAs and proteins, respectively, within the interactome highlighting their potential roles in the cardiovascular diseases, neurological disorders, and cancers. The role of proteins like METTL3 and AGO2 and miRNAs such as hsa-miR-484 and hsa-miR-30 families, hsa-mir-126-5p has been discussed contextually. Additionally, we discovered simple sequence repeats in the consensus patterns having unexplored functional roles. Our observations provide new insights into the extracellular miRNA-protein interactions that may drive disease initiation and progression offering potential avenues for overcoming challenges like therapy relapse and drug inefficacy. The results of our analysis are available in the miRPin database (https://www.mirna.in/miRPin).
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Affiliation(s)
- Vishal Kumar Sahu
- Cancer and Translational Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
| | - Subhayan Sur
- Cancer and Translational Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
| | - Sanjana Agarwal
- Cancer and Translational Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
| | - Harishkumar Madhyastha
- Department of Cardiovascular Physiology, Faculty of Medicine, University of Miyazaki, Miyazaki 8891692, Japan
| | - Amit Ranjan
- Cancer and Translational Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India.
| | - Soumya Basu
- Cancer and Translational Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India.
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2
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Kim G, Cha Y, Baek SH. Identification of KANK1 as a tumor suppressor gene in pancreatic ductal adenocarcinoma. Biochem Biophys Res Commun 2025; 766:151885. [PMID: 40288262 DOI: 10.1016/j.bbrc.2025.151885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2025] [Accepted: 04/23/2025] [Indexed: 04/29/2025]
Abstract
Pancreatic cancer is a highly lethal malignancy with poor survival outcomes, primarily due to late-stage diagnosis and resistance to conventional therapies. Identifying key oncogenes and tumor suppressor genes is therefore critical for the development of effective treatment strategies. In this study, we identified KANK1 as a novel tumor suppressor gene in pancreatic ductal adenocarcinoma (PDAC) through an integrated mRNA-protein abundance correlation analysis. Elevated KANK1 expression was consistently associated with improved patient survival across multiple datasets, whereas its expression was markedly reduced in pancreatic tumors compared to normal tissues. Single-cell RNA sequencing and immunoblot analyses confirmed the downregulation of KANK1 at both the mRNA and protein levels in PDAC. Further investigation revealed that KANK1 downregulation is driven by copy number loss and tumor hypoxia, supported by data from the TCGA and CCLE databases and validated experimentally under hypoxic conditions. Functional assays demonstrated that KANK1 knockdown promotes pancreatic cancer cell proliferation and migration, along with activation of ERK signaling. Collectively, our findings establish KANK1 as a tumor suppressor in PDAC, whose loss facilitates tumor progression and presents a potential therapeutic target for pancreatic cancer treatment.
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Affiliation(s)
- Gibeom Kim
- Creative Research Initiatives Center for Epigenetic Code and Diseases, Seoul National University, Seoul, 08826, South Korea; Department of Biological Sciences, Seoul National University, Seoul, 08826, South Korea
| | - Yoonho Cha
- Creative Research Initiatives Center for Epigenetic Code and Diseases, Seoul National University, Seoul, 08826, South Korea; Department of Biological Sciences, Seoul National University, Seoul, 08826, South Korea
| | - Sung Hee Baek
- Creative Research Initiatives Center for Epigenetic Code and Diseases, Seoul National University, Seoul, 08826, South Korea; Department of Biological Sciences, Seoul National University, Seoul, 08826, South Korea.
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3
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Ma L, Mao JH, Barcellos-Hoff MH. Systemic inflammation in response to radiation drives the genesis of an immunosuppressed tumor microenvironment. Neoplasia 2025; 64:101164. [PMID: 40184664 PMCID: PMC11999686 DOI: 10.1016/j.neo.2025.101164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 03/24/2025] [Accepted: 03/27/2025] [Indexed: 04/07/2025]
Abstract
The composition of the tumor immune microenvironment has become a major determinant of response to therapy, particularly immunotherapy. Clinically, a tumor microenvironment lacking lymphocytes, so-called "cold" tumors, are considered poor candidates for immune checkpoint inhibition. In this review, we describe the diversity of the tumor immune microenvironment in breast cancer and how radiation exposure alters carcinogenesis. We review the development and use of a radiation-genetic mammary chimera model to clarify the mechanism by which radiation acts. Using the chimera model, we demonstrate that systemic inflammation elicited by a low dose of radiation is key to the construction of an immunosuppressive tumor microenvironment, resulting in aggressive, rapidly growing tumors lacking lymphocytes. Our experimental studies inform the non-mutagenic mechanisms by which radiation affects cancer and provide insight into the genesis of cold tumors.
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Affiliation(s)
- Lin Ma
- Department of Stomatology, Shenzhen University General Hospital, Shenzhen University, Shenzhen, 518055, China
| | - Jian-Hua Mao
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
| | - Mary Helen Barcellos-Hoff
- Department of Radiation Oncology, School of Medicine, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA 94143 USA.
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4
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Alvarado-Ortiz E, Castañeda-Patlán MC, Moreno-Londoño AP, Tinajero-Rodríguez JM, Briseño-Díaz P, Sarabia-Sánchez MA, Vargas M, Ortiz-Sánchez E, Robles-Flores M. Non-canonical Wnt co-receptors ROR1/ROR2 are differentially regulated by hypoxia in colon cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2025; 1872:119968. [PMID: 40268059 DOI: 10.1016/j.bbamcr.2025.119968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 04/16/2025] [Accepted: 04/18/2025] [Indexed: 04/25/2025]
Abstract
ROR1 and ROR2 co-receptors are transducers of non-canonical Wnt responses that promote an aggressive phenotype in several cancer types, including colon cancer. It has been demonstrated that hypoxia promotes tumor progression through the action of Hypoxia Inducible Factors (HIFs). An in silico analysis revealed that ROR2 is overexpressed in the advanced clinical stages of colon cancer. In line with this, ROR1 and ROR2 were found to be only expressed in malignant colon cells compared to non-malignant ones. The blockade of either ROR1 or ROR2 impaired colon cancer cells' colony formation abilities and the migration capacity of them. Additionally, the silencing of the ROR2 co-receptor blocked the metastatic ability of colon cancer cells in a xenografted mice model. We found that while silencing HIF-1α did not significantly reduce ROR1 or ROR2 expression, inhibiting HIF-2α and HIF-3α expression greatly decreased the protein levels of both co-receptors in colon cancer cells. The HIF-1α subunit expression is induced in acute hypoxia, whereas HIF-2α and HIF-3α show higher activity in chronic hypoxia, which may be functionally relevant since hypoxia induced a decrease in the constitutive active β-catenin transcriptional activity in SW480 cells. While both ROR1 and ROR2 stimulate proliferation and migration under normoxic conditions, the exposure of cells to hypoxia increased the expression of ROR1 or ROR2, depending on the Wnt cellular context, Thus, our results indicate that hypoxia partially represses β-catenin transcriptional activity and activates non-canonical Wnt signaling by regulating ROR1/ROR2 expression to induce an aggressive migrating and metastatic phenotype in colon cancer cells.
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Affiliation(s)
- Eduardo Alvarado-Ortiz
- Programa de Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Mexico City, Mexico; Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | | | | | | | - Paola Briseño-Díaz
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Miguel Angel Sarabia-Sánchez
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Miguel Vargas
- Department of Molecular Biomedicine, Center for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV-IPN), Mexico
| | - Elizabeth Ortiz-Sánchez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Mexico City, Mexico
| | - Martha Robles-Flores
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico.
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5
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Smith SC, Diaz-Perez JA, Mochel MC, Billings SD, Fernandez L, Poklepovic AS. A High-grade PML::JAK1 Fusion Sarcoma. Am J Surg Pathol 2025; 49:633-635. [PMID: 39494835 DOI: 10.1097/pas.0000000000002326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2024]
Affiliation(s)
- Steven Christopher Smith
- Department of Pathology, VCU School of Medicine, Richmond, VA
- Department of Surgery, VCU School of Medicine, Richmond, VA
- VCU Massey Comprehensive Cancer Center, VCU Health, Richmond, VA
| | | | | | | | - Leopoldo Fernandez
- Department of Surgery, VCU School of Medicine, Richmond, VA
- VCU Massey Comprehensive Cancer Center, VCU Health, Richmond, VA
| | - Andrew S Poklepovic
- Division of Hematology, Oncology, and Palliative Care, Department of Medicine VCU School of Medicine Richmond, VA
- VCU Massey Comprehensive Cancer Center, VCU Health, Richmond, VA
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6
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Ellington CN, Lengerich BJ, Watkins TBK, Yang J, Adduri AK, Mahbub S, Xiao H, Kellis M, Xing EP. Learning to estimate sample-specific transcriptional networks for 7,000 tumors. Proc Natl Acad Sci U S A 2025; 122:e2411930122. [PMID: 40408406 DOI: 10.1073/pnas.2411930122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 04/06/2025] [Indexed: 05/25/2025] Open
Abstract
Cancers are shaped by somatic mutations, microenvironment, and patient background, each altering gene expression and regulation in complex ways, resulting in heterogeneous cellular states and dynamics. Inferring gene regulatory networks (GRNs) from expression data can help characterize this regulation-driven heterogeneity, but network inference requires many statistical samples, limiting GRNs to cluster-level analyses that ignore intracluster heterogeneity. We propose to move beyond coarse analyses of predefined subgroups by using contextualized learning, a multitask learning paradigm that uses multiview contexts including phenotypic, molecular, and environmental information to infer personalized models. With sample-specific contexts, contextualization enables sample-specific models and even generalizes at test time to predict network models for entirely unseen contexts. We unify three network model classes (Correlation, Markov, and Neighborhood Selection) and estimate context-specific GRNs for 7,997 tumors across 25 tumor types, using copy number and driver mutation profiles, tumor microenvironment, and patient demographics as model context. Our generative modeling approach allows us to predict GRNs for unseen tumor types based on a pan-cancer model of how somatic mutations affect gene regulation. Finally, contextualized networks enable GRN-based precision oncology by providing a structured view of expression dynamics at sample-specific resolution, explaining known biomarkers in terms of network-mediated effects and leading to subtypings that improve survival prognosis. We provide a SKLearn-style Python package https://contextualized.ml for learning and analyzing contextualized models, as well as interactive plotting tools for pan-cancer data exploration at https://github.com/cnellington/CancerContextualized.
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Affiliation(s)
- Caleb N Ellington
- Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213
| | - Benjamin J Lengerich
- Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139
- Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142
| | - Thomas B K Watkins
- Cancer Institute, University College London, London WC1E 6DD, United Kingdom
| | - Jiekun Yang
- Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139
- Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142
| | - Abhinav K Adduri
- Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213
| | - Sazan Mahbub
- Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213
| | - Hanxi Xiao
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260
| | - Manolis Kellis
- Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139
- Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142
| | - Eric P Xing
- Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213
- Machine Learning Department, Mohamed bin Zayed University of Artificial Intelligence, Masdar City SE45 05, Abu Dhabi, United Arab Emirates
- GenBio AI Inc., Palo Alto, CA 94301
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7
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Schiele P, Japp AS, Stark R, Sattelberg JJ, Nikolaou C, Kornhuber G, Abbasi P, Ding N, Rosnev S, Meinke S, Mühle K, Loyal L, Braun J, Dingeldey M, Durlanik S, Matzmohr N, Ponikwicka-Tyszko D, Wolczynski S, Rahman NA, Taniuchi I, Schlickeiser S, Giesecke-Thiel C, Blankenstein T, Na IK, Thiel A, Frentsch M. CD8 + T cell-derived CD40L mediates noncanonical cytotoxicity in CD40-expressing cancer cells. SCIENCE ADVANCES 2025; 11:eadr9331. [PMID: 40397730 DOI: 10.1126/sciadv.adr9331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 04/17/2025] [Indexed: 05/23/2025]
Abstract
T cells and their effector functions, in particular the canonical cytotoxicity of CD8+ T cells involving perforin, granzymes, Fas ligand (FasL), and tumor necrosis factor related apoptosis inducing ligand (TRAIL), are crucial for tumor immunity. Here, we reveal a previously unidentified mechanism by which CD40L-expressing CD8+ T cells induce cytotoxicity in cancer cells. In murine models, up to 50% of tumor-specific CD8+ T cells expressed CD40L, and conditional CD40L ablation in CD8+ T cells alone led to tumor formation. Mechanistically, CD40L+CD8+ T cells can induce cell death in CD40-expressing cancer cells by triggering caspase-8 activation. We demonstrate that a gene signature for resistance to CD40 signaling-induced cell death strongly correlates with worse survival in different human cancer cohorts. Our results introduce CD40L as a rather counterintuitive, noncanonical cytotoxic factor that complements the capabilities of CD8+ T cells to combat cancers and has the potential to enhance the efficacy of immunotherapies.
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Affiliation(s)
- Phillip Schiele
- Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Alberto Sada Japp
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Captain T Cell GmbH, 12529 Berlin, Germany
| | - Regina Stark
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Tissue Immunology, BIH Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Joanna J Sattelberg
- Max-Delbrück-Center for Molecular Medicine and Institute for Immunology, Charité-Universitätsmedizin Berlin, 13125 Berlin, Germany
| | - Christos Nikolaou
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Gereon Kornhuber
- Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Parya Abbasi
- Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Nina Ding
- Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Stanislav Rosnev
- Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Stefan Meinke
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Kerstin Mühle
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Lucie Loyal
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Si-M/"Der Simulierte Mensch," Technische Universität Berlin and Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Julian Braun
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Si-M/"Der Simulierte Mensch," Technische Universität Berlin and Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Manuela Dingeldey
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Si-M/"Der Simulierte Mensch," Technische Universität Berlin and Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Sibel Durlanik
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Nadine Matzmohr
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Donata Ponikwicka-Tyszko
- Institute of Biomedicine, University of Turku, 20520 Turku, Finland
- Department of Biology and Pathology of Human Reproduction, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, 10-748 Olsztyn, Poland
| | - Slawomir Wolczynski
- Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, 15-276 Bialystok, Poland
| | - Nafis A Rahman
- Institute of Biomedicine, University of Turku, 20520 Turku, Finland
- Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, 15-276 Bialystok, Poland
| | - Ichiro Taniuchi
- RIKEN Research Center for Allergy and Immunology, Yokohama 230-0045, Japan
| | - Stephan Schlickeiser
- Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate members of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | | | - Thomas Blankenstein
- Max-Delbrück-Center for Molecular Medicine and Institute for Immunology, Charité-Universitätsmedizin Berlin, 13125 Berlin, Germany
| | - Il-Kang Na
- Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Department of Hematology, Oncology and Tumor Immunology, and ECRC Experimental and Clinical Research Center, both Charité-Universitätsmedizin Berlin, Corporate members of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Cancer Consortium (DKTK), Berlin, Germany
- ECRC Experimental and Clinical Research Center, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Andreas Thiel
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Si-M/"Der Simulierte Mensch," Technische Universität Berlin and Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Marco Frentsch
- Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
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Tyutyunyk-Massey L, Chen Z, Liu X, Kawakami M, Harned A, Ng Y, Luke B, Okpechi SC, Ogunlade B, Alfaro Y, Weigert R, Narayan K, Liu X, Dmitrovsky E. CDK2 inhibition produces a persistent population of polyploid cancer cells. JCI Insight 2025; 10:e189901. [PMID: 40232858 DOI: 10.1172/jci.insight.189901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 04/09/2025] [Indexed: 04/17/2025] Open
Abstract
Aneuploidy, a cancer hallmark, drives chromosomal instability, drug resistance, and clinically aggressive tumors. Cyclin-dependent kinase 2 (CDK2) antagonism with independent inhibitors or CDK2 knockdown triggered anaphase catastrophe. This disrupts supernumerary centrosome clustering, causing multipolar division and apoptosis. Time-lapse fluorescence microscopy of fluorescent ubiquitination-based cell cycle indicator (FUCCI) cell cycle probes transduced into aneuploid lung cancer cells revealed distinct fates of bipolar and polyploid cells after CDK2 inhibition. Apoptosis occurred in multipolar progeny but was repressed in persistent polyploid cancer cells. RNA-Seq analyses after CDK2 inhibition of 4N versus 2N lung cancer cells were enriched for CDK1 pathway and KIF family members. The Cancer Genome Atlas (TCGA) analysis of lung cancers indicated that CDK1 and KIF family member overexpression was associated with an unfavorable survival. Intravital microscopy of transplanted lung cancer cells in mice extended findings from the in vitro to in vivo settings. CDK2 inhibition of tumor-bearing mice produced polyploid cancer cells in vivo. These cancer cells were resistant to apoptosis and proliferated despite CDK2 inhibition. In contrast, polyploid populations were rarely detected in CDK2-inhibited human alveolar epithelial cells. These findings are translationally relevant. Combined targeting of CDK2 with CDK1 or kinesin family member antagonists should eliminate polyploid cancer cells, promote apoptosis, and augment antineoplastic effects.
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Affiliation(s)
| | | | | | | | - Adam Harned
- Center for Molecular Microscopy, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Yeap Ng
- Laboratory of Cellular and Molecular Biology, and
- Intravital Microscopy Core, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Brian Luke
- Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | | | | | | | - Roberto Weigert
- Laboratory of Cellular and Molecular Biology, and
- Intravital Microscopy Core, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Kedar Narayan
- Center for Molecular Microscopy, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Xi Liu
- Molecular Pharmacology Program and
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9
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Wu J, Chen S, Xu R, Chen Y, Guo J, Li J, Zeng X, Wang B, Zhu X. Multidimensional investigation of thyroid hormones and prostate cancer: insights from NHANES, Mendelian randomization, genetic markers, and bioinformatics analyses. Discov Oncol 2025; 16:843. [PMID: 40397285 PMCID: PMC12095733 DOI: 10.1007/s12672-025-02672-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Accepted: 05/12/2025] [Indexed: 05/22/2025] Open
Abstract
BACKGROUND Prostate cancer remains a major global health burden for men, with its incidence and mortality steadily rising. Thyroid hormones, critical regulators of metabolism and cell growth, have been implicated in tumorigenesis, yet their specific role in prostate cancer risk remains unclear. This study systematically investigates the relationship between thyroid hormones and prostate cancer using multidimensional approaches. METHODS A three-phase study design was employed: (1) A cross-sectional analysis of The National Health and Nutrition Examination Survey (NHANES) data to examine thyroid hormone levels (FT3 and T3) and prostate cancer risk; (2) Mendelian randomization (MR) analysis using genome-wide association studies (GWAS) data to explore causal relationships; (3) Bioinformatics analyses to annotate key Single Nucleotide Polymorphism(SNPs), identify related genes, and assess their biological roles in prostate cancer. RESULTS Observational analysis revealed significantly lower FT3 and T3 levels in high-risk prostate cancer patients, with adjusted models confirming an inverse association (p < 0.001). MR analysis supported a causal relationship between thyroid hormone replacement therapy and reduced prostate cancer risk (b < 0, p < 0.05). Four key genes-ADM5, INPP5B, NEURL4, and TYK2-were identified as downregulated in prostate cancer tissues, with prognostic and immune regulatory implications. CONCLUSIONS Thyroid hormones exhibit a protective role against prostate cancer. ADM5, INPP5B, NEURL4, and TYK2 emerge as potential biomarkers and therapeutic targets, warranting further mechanistic and clinical validation.
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Affiliation(s)
- Jinhai Wu
- Department of Urology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China
| | - Sian Chen
- Department of Urology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China
| | - Ran Xu
- Department of Urology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yanfei Chen
- Department of Urology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China
| | - Jiadin Guo
- Department of Urology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China
| | - Jing Li
- Department of Urology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China
| | - Xiheng Zeng
- Department of Urology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China
| | - Bin Wang
- Department of Urology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China.
| | - Xuejin Zhu
- Department of Urology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China.
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10
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Shankar K, Walker SE. Analysis of divergent gene expression between HPV + and HPV- head and neck squamous cell carcinoma patients. Infect Agent Cancer 2025; 20:31. [PMID: 40400005 PMCID: PMC12096591 DOI: 10.1186/s13027-025-00663-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2025] [Accepted: 05/13/2025] [Indexed: 05/23/2025] Open
Abstract
Human Papillomavirus (HPV) is a non-enveloped virus with a circular double-stranded DNA genome. It is one of the most common sexually transmitted infections, with high-risk types such as HPV-16 and HPV-18 linked to anogenital and head and neck squamous cell carcinomas (HNSCC). HNSCC includes cancers of the oral cavity, pharynx, larynx, and related regions, caused by carcinogens or persistent viral infections. HPV-positive (HPV+) HNSCC cases are more prevalent in Western countries and exhibit better prognosis and treatment response compared to HPV-negative (HPV-) cases. These differences suggest distinct fundamental differences between each subtype. This study analyzed RNA-seq data from the PanCancer Atlas 2018 dataset to investigate molecular distinctions between HPV + and HPV- HNSCC. Using dimensionality reduction techniques such as Principal Component Analysis (PCA) and Uniform Manifold Approximation and Projection (UMAP), a clear clustering of HPV + cases was observed, suggesting a unique gene expression profile. HPV + tumors exhibited upregulation of genes involved in nucleic acid processing and downregulation of genes associated with apoptosis and epidermis development. These findings underscore the biological differences between HPV + and HPV- HNSCC, offering insights into HPV-driven oncogenesis. Understanding these distinctions may improve patient stratification and inform targeted therapeutic strategies for HNSCC.
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Affiliation(s)
- Kasturika Shankar
- Department of Biological Sciences, The State University of New York at Buffalo, Buffalo, NY, USA.
| | - Sarah E Walker
- Department of Biological Sciences, The State University of New York at Buffalo, Buffalo, NY, USA.
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11
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Chen F, Zhang Y, Li W, Sedlazeck FJ, Shen L, Creighton CJ. Global DNA methylation differences involving germline structural variation impact gene expression in pediatric brain tumors. Nat Commun 2025; 16:4713. [PMID: 40399292 PMCID: PMC12095544 DOI: 10.1038/s41467-025-60110-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 05/13/2025] [Indexed: 05/23/2025] Open
Abstract
The extent of genetic variation and its influence on gene expression across multiple tissue and cellular contexts is still being characterized, with germline Structural Variants (SVs) being historically understudied. DNA methylation also represents a component of normal germline variation across individuals. Here, we combine germline SVs (by short-read sequencing) with tumor DNA methylation across 1292 pediatric brain tumor patients. For thousands of methylation probes for CpG Islands (CGIs) or enhancers, rare and common SV breakpoints upstream or downstream associate with differential methylation in tumors spanning various histologic types, a significant subset involving genes with SV-associated differential expression. Cancer predisposition genes involving SV-associated differential methylation and expression include MSH2, RSPA, and PALB2. SV breakpoints falling within CGIs or histone marks H3K36me3 or H3K9me3 associate with differential CGI methylation. Genes with SVs and CGI methylation associated with patient survival include POLD4. Our results capture a class of normal phenotypic variation having disease implications.
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Affiliation(s)
- Fengju Chen
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Yiqun Zhang
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Wei Li
- Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, 92697, USA
| | - Fritz J Sedlazeck
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA
- Department of Computer Science, Rice University, Houston, TX, 77005, USA
| | - Lanlan Shen
- USDA Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Chad J Creighton
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
- Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA.
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12
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Meng C, Lin K, Shi W, Teng H, Wan X, DeBruine A, Wang Y, Liang X, Leo J, Chen F, Gu Q, Zhang J, Van V, Maldonado KL, Gan B, Ma L, Lu Y, Zhao D. Histone methyltransferase ASH1L primes metastases and metabolic reprogramming of macrophages in the bone niche. Nat Commun 2025; 16:4681. [PMID: 40394007 PMCID: PMC12092585 DOI: 10.1038/s41467-025-59381-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 04/22/2025] [Indexed: 05/22/2025] Open
Abstract
Bone metastasis is a major cause of cancer death; however, the epigenetic determinants driving this process remain elusive. Here, we report that histone methyltransferase ASH1L is genetically amplified and is required for bone metastasis in men with prostate cancer. ASH1L rewires histone methylations and cooperates with HIF-1α to induce pro-metastatic transcriptome in invading cancer cells, resulting in monocyte differentiation into lipid-associated macrophage (LA-TAM) and enhancing their pro-tumoral phenotype in the metastatic bone niche. We identified IGF-2 as a direct target of ASH1L/HIF-1α and mediates LA-TAMs' differentiation and phenotypic changes by reprogramming oxidative phosphorylation. Pharmacologic inhibition of the ASH1L-HIF-1α-macrophages axis elicits robust anti-metastasis responses in preclinical models. Our study demonstrates epigenetic alterations in cancer cells reprogram metabolism and features of myeloid components, facilitating metastatic outgrowth. It establishes ASH1L as an epigenetic driver priming metastasis and macrophage plasticity in the bone niche, providing a bona fide therapeutic target in metastatic malignancies.
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Affiliation(s)
- Chenling Meng
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Kevin Lin
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Wei Shi
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Hongqi Teng
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Xinhai Wan
- Department of Endocrine Neoplasia & Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Anna DeBruine
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Yin Wang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Xin Liang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Javier Leo
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Feiyu Chen
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Qianlin Gu
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Jie Zhang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Vivien Van
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Kiersten L Maldonado
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Boyi Gan
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Li Ma
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Yue Lu
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| | - Di Zhao
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
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13
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Akita Y, Velaga R, Iwase M, Shimada S, Kikumori T, Takeuchi D, Takano Y, Ichikawa T, Ebata T, Masuda N. Prognostici of ER-staining patterns and heterogeneity of ER positive HER2 negative breast cancer. Breast Cancer 2025:10.1007/s12282-025-01716-4. [PMID: 40382758 DOI: 10.1007/s12282-025-01716-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 04/30/2025] [Indexed: 05/20/2025]
Abstract
BACKGROUND Estrogen receptor (ER) expression is critical in breast cancer treatment. While low ER (1-9%) resembles triple-negative cancer with chemotherapy efficacy, the significance of "intermediate expression" (≥ 10%) and the therapeutic efficacy remain unclear. This study explores the differences in staining patterns and molecular characteristics of ER-low to intermediate expression to guide treatment. METHODS A total of 104 breast cancer patients treated between January 2008 and July 2024 with an Allred Proportion Score (PS) of 2-4 were included. PS2 (n = 21) was classified as ER-low, while PS3 (n = 26) and PS4 (n = 57) as ER-intermediate (ER-int). ER-int was further divided by ER staining pattern: "Island" (heterogeneous) and "Scatter," (uniform) subgroups. The prognosis, clinical factors, and gene expression profiles (n = 11) were analyzed. RESULTS The Island subgroup was associated with poorest prognosis (p = 0.0116), particularly among the patients treated with endocrine-only treatment patients (p < 0.0001). Elevated tumor-infiltrating lymphocyte (TIL) levels correlated with worse prognosis in endocrine-only treatment patients (p < 0.0043), with TIL levels highest in ER-low, followed by Island and Scatter subgroups. Island tumors were enriched in CD36, GZMB, and type I interferon genes; additionally, 23 "ISLAND" genes showed significant prognostic differences in the TCGA BRCA ER-int (10-69%) cohort. CONCLUSION This study emphasizes the importance of recognizing heterogeneity within the ER-int subtype. Identifying distinct ER staining patterns and prognostic significance of TILs and transcriptome in ER-int tumors suggests the need for individualized treatment strategies for Island subtype.
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Affiliation(s)
- Yumiko Akita
- Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Ravi Velaga
- Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Madoka Iwase
- Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Satoko Shimada
- Department of Pathology, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Toyone Kikumori
- Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Dai Takeuchi
- Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Yuko Takano
- Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Takahiro Ichikawa
- Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Tomoki Ebata
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Norikazu Masuda
- Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.
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14
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Chen F, Li H, Wang Y, Tang X, Lin K, Li Q, Meng C, Shi W, Leo J, Liang X, Zhang J, Van V, Mahmud I, Wei B, Lorenzi PL, Raso MG, Aparicio A, Lu Y, Frigo DE, Gan B, Zhao D. CHD1 loss reprograms SREBP2-driven cholesterol synthesis to fuel androgen-responsive growth and castration resistance in SPOP-mutated prostate tumors. NATURE CANCER 2025:10.1038/s43018-025-00952-z. [PMID: 40360905 DOI: 10.1038/s43018-025-00952-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 03/18/2025] [Indexed: 05/15/2025]
Abstract
Despite undergoing castration, most individuals with prostate cancer (PCa) experience progression to castration-resistant PCa (CRPC), in which the androgen receptor (AR) remains an important driver. Concurrent genetic alterations in SPOP and CHD1 define a unique subtype of PCa, but their interactions in tumor progression and therapy response remain unclear. Here, we provide genetic evidence supporting that CHD1 loss accelerates disease progression and confers resistance to castration in males with SPOP-mutated PCa. By leveraging genetic engineering and multiomics, we uncovered a noncanonical function of CHD1 in lipid metabolism reprogramming via repressing the SREBP2 transcriptome. Loss of CHD1 induces cholesterol production, supplies intratumoral androgen biosynthesis and enhances AR activity, leading to castration resistance of SPOP-mutated PCa. Combining anti-androgen therapy with cholesterol-lowering drugs showed synergistic and durable activity against CRPC harboring CHD1 loss and SPOP mutations. These findings advance our understanding of an emerging PCa subtype and offer biomarker-driven combinatorial treatment strategies for men with CRPC.
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Affiliation(s)
- Feiyu Chen
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Haoyan Li
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yin Wang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ximing Tang
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kevin Lin
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Qidong Li
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Chenling Meng
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Wei Shi
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Javier Leo
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xin Liang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jie Zhang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vivien Van
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Iqbal Mahmud
- Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bo Wei
- Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Philip L Lorenzi
- Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Maria G Raso
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ana Aparicio
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yue Lu
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Daniel E Frigo
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Boyi Gan
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Di Zhao
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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15
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Moufarrij S, Dopeso H, Brown DN, Green H, Gill K, Tengelin J, Brodeur MN, Zammarrelli WA, Varice N, Wu M, Jungbluth A, Zhu Y, Chen X, Da Cruz Paula A, Basili T, de Stanchina E, Abu-Rustum NR, Aghajanian C, Ellenson LH, Chui MH, Weigelt B. TROP2 expression and therapeutic targeting in uterine carcinosarcoma. Gynecol Oncol 2025; 197:129-138. [PMID: 40344963 DOI: 10.1016/j.ygyno.2025.04.590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 04/22/2025] [Accepted: 04/25/2025] [Indexed: 05/11/2025]
Abstract
OBJECTIVE Uterine carcinosarcoma (UCS) is a rare and aggressive type of endometrial carcinoma (EC), and novel therapeutic strategies are needed. We sought to assess TROP2 expression in archival UCSs and TROP2 antibody-drug conjugate (ADC) targeting in patient-derived UCS organoid (PDO) and xenograft (PDX) models. METHODS TROP2 protein (immunohistochemistry) and mRNA (qRT-PCR) expression were assessed in 72 archival UCS tissues. Nine UCS PDO models were established and molecularly characterized by panel sequencing; then, TROP2 levels were determined and the efficacy of the TROP2 ADC sacituzumab govitecan (SG) defined in the UCS PDO and PDX models (n = 2). RESULTS TROP2 protein and mRNA expression were detected in ≥90 % of primary UCSs, and those with a predominant carcinomatous component or with homologous differentiation had higher TROP2 expression than those with a predominant sarcomatous component or with heterologous differentiation (p < 0.001 and p = 0.022, respectively). UCS PDOs displayed TROP2 expression and molecular profiles (median 88 %, range 50-100 % of mutation in primary UCSs present in PDOs) reflective of their respective primary UCSs. All 9 UCS PDOs responded in a dose-dependent manner to SG treatment, with a median IC50 of 167.7pM (range 51.4pM-3.2 nM). In addition, both UCS PDX models with high and low TROP2 protein expression had a significant reduction in tumor volume with SG treatment (p = 0.03 and p = 0.02, respectively). CONCLUSIONS We demonstrate that the majority of UCSs have detectable TROP2 expression. Our findings on the SG response in UCS PDO and PDX models warrant further studies on TROP2 targeting for patients with this aggressive disease.
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Affiliation(s)
- Sara Moufarrij
- Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Higinio Dopeso
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - David N Brown
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Hunter Green
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kaitlyn Gill
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Julia Tengelin
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Melica N Brodeur
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - William A Zammarrelli
- Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nancy Varice
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michelle Wu
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Achim Jungbluth
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yingjie Zhu
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Xiaoping Chen
- Antitumor Assessment Core Facility, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Arnaud Da Cruz Paula
- Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Thais Basili
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Elisa de Stanchina
- Antitumor Assessment Core Facility, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nadeem R Abu-Rustum
- Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of OB/GYN, Weill Cornell Medical College, New York, NY, USA
| | - Carol Aghajanian
- Gynecologic Medical Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Lora H Ellenson
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - M Herman Chui
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Britta Weigelt
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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16
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Nadendla EK, Tweedell RE, Kasof G, Kanneganti TD. Caspases: structural and molecular mechanisms and functions in cell death, innate immunity, and disease. Cell Discov 2025; 11:42. [PMID: 40325022 PMCID: PMC12052993 DOI: 10.1038/s41421-025-00791-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 03/05/2025] [Indexed: 05/07/2025] Open
Abstract
Caspases are critical regulators of cell death, development, innate immunity, host defense, and disease. Upon detection of pathogens, damage-associated molecular patterns, cytokines, or other homeostatic disruptions, innate immune sensors, such as NLRs, activate caspases to initiate distinct regulated cell death pathways, including non-lytic (apoptosis) and innate immune lytic (pyroptosis and PANoptosis) pathways. These cell death pathways are driven by specific caspases and distinguished by their unique molecular mechanisms, supramolecular complexes, and enzymatic properties. Traditionally, caspases are classified as either apoptotic (caspase-2, -3, -6, -7, -8, -9, and -10) or inflammatory (caspase-1, -4, -5, and -11). However, extensive data from the past decades have shown that apoptotic caspases can also drive lytic inflammatory cell death downstream of innate immune sensing and inflammatory responses, such as in the case of caspase-3, -6, -7, and -8. Therefore, more inclusive classification systems based on function, substrate specificity, or the presence of pro-domains have been proposed to better reflect the multifaceted roles of caspases. In this review, we categorize caspases into CARD-, DED-, and short/no pro-domain-containing groups and examine their critical functions in innate immunity and cell death, along with their structural and molecular mechanisms, including active site/exosite properties and substrates. Additionally, we highlight the emerging roles of caspases in cellular homeostasis and therapeutic targeting. Given the clinical relevance of caspases across multiple diseases, improved understanding of these proteins and their structure-function relationships is critical for developing effective treatment strategies.
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Affiliation(s)
- Eswar Kumar Nadendla
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Rebecca E Tweedell
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Gary Kasof
- Cell Signaling Technology, Danvers, MA, USA
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17
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Iyer AR, Gurumurthy A, Chu SCA, Kodgule R, Aguilar AR, Saari T, Ramzan A, Rosa J, Gupta J, Emmanuel A, Hall CN, Runge JS, Owczarczyk AB, Cho JW, Weiss MB, Anyoha R, Sikkink K, Gemus S, Fulco CP, Perry AM, Schmitt AD, Engreitz JM, Brown NA, Cieslik MP, Ryan RJ. Selective Enhancer Dependencies in MYC-Intact and MYC-Rearranged Germinal Center B-cell Diffuse Large B-cell Lymphoma. Blood Cancer Discov 2025; 6:233-253. [PMID: 40067173 PMCID: PMC12050968 DOI: 10.1158/2643-3230.bcd-24-0126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 12/28/2024] [Accepted: 03/10/2025] [Indexed: 03/15/2025] Open
Abstract
SIGNIFICANCE Aberrant MYC activity defines the most aggressive GCB-DLBCLs. We characterized a mechanism of MYC transcriptional activation via a native enhancer that is active in MYC-intact GCB-DLBCL, establishing fitness-sustaining cis- and trans-regulatory circuitry in GCB-DLBCL models that lack MYC enhancer-hijacking rearrangement. See related commentary by Mulet-Lazaro and Delwel, p. 149.
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Affiliation(s)
- Ashwin R. Iyer
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Aishwarya Gurumurthy
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Shih-Chun A. Chu
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Rohan Kodgule
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Athalee R. Aguilar
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Travis Saari
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Abdullah Ramzan
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Jan Rosa
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Juhi Gupta
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Arvind Emmanuel
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Cody N. Hall
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - John S. Runge
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Anna B. Owczarczyk
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Jang W. Cho
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Matthew B. Weiss
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Rockwell Anyoha
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts
| | | | | | - Charles P. Fulco
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts
| | - Anamarija M. Perry
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | | | - Jesse M. Engreitz
- Department of Genetics, Stanford University School of Medicine, Stanford, California
- BASE Initiative, Betty Irene Moore Children’s Heart Center, Lucile Packard Children’s Hospital, Stanford, California
- Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Noah A. Brown
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Marcin P. Cieslik
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Russell J.H. Ryan
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
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18
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Haferssas D, Dubuissez M, Barrera-Chimal J, Messmer C, Affar EB, Larrivée B, Liu XS, Gerarduzzi C. FLT4 activation promotes acute lymphoid leukemia survival through stabilization of MDM2/MDMX and inactivation of p53. Oncogenesis 2025; 14:14. [PMID: 40316529 PMCID: PMC12048674 DOI: 10.1038/s41389-025-00552-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 02/21/2025] [Accepted: 03/20/2025] [Indexed: 05/04/2025] Open
Abstract
Aberrant Receptor Tyrosine Kinase (RTK) signaling allows cancer cells to modulate survival, proliferation, and death, leading to tumorigenesis and chemoresistance. In leukemia, the RTK FMS-Related Tyrosine Kinase 4 (FLT4) (also known as VEGFR3, Vascular Endothelial Growth Factor Receptor- 3) is deregulated and correlates with cancer progression. However, the underlying consequences of its deregulation remain to be determined. Moreover, chemotherapy treatment requires that cancer cells retain a wild-type p53 to respond to DNA damage by tumor-suppressing activities, i.e. apoptosis. p53 activity is predominantly limited by its two major negative regulators, MDM2 and MDMX, which inactivate p53 by promoting its degradation and/or cytoplasmic localization. In this study, we have shown that activation of FLT4 by either overexpression or binding of its ligand, VEGFC, increases MDM2/MDMX stability, inactivates p53, and leads to resistance to DNA-damaging therapies. Moreover, we found that MDMX Ser-314 phosphorylation, a consensus sequence of CDK4/6, increases MDMX stability, which subsequently affects MDM2 and p53 degradation and could be reversed by the CDK4/6 inhibitor Palbociclib. More importantly, leukemic cells treated with Palbociclib were more susceptible to DNA-damaging induction of apoptosis and had reduced cell proliferation. Leukemic cells overexpressing FLT4 displayed accelerated proliferation when injected into NOD-SCID mice as compared to wild-type cells. Altogether, our research proposes an innovative way to reactivate p53 in leukemia through the pharmacological inhibition of FLT4 signaling, which could serve as a potential treatment option. Schematic representation of FLT4-mediated MDM2/MDMX complex stabilization and suppression of p53 activity. VEGFC triggers FLT4 activation, leading to CDK4/6 activation, which phosphorylates MDMX on Ser-314. As a result, MDMX levels increase and bind to MDM2, stabilizing the MDM2/MDMX complex. This complex binds to p53, facilitating its suppression by reducing its transcriptional activity or enhancing its export to the cytoplasm for proteasomal degradation. Consequently, p53 inactivation promotes their survival, proliferation, and resistance to chemotherapy-induced apoptosis. The figure was created in BioRender.com.
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Affiliation(s)
- Djazia Haferssas
- Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
- Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Centre Affilié à l'Université de Montréal, Montréal, QC, Canada
| | - Marion Dubuissez
- Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Centre Affilié à l'Université de Montréal, Montréal, QC, Canada
- Département de Microbiologie et Immunologie, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
| | - Jonatan Barrera-Chimal
- Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Centre Affilié à l'Université de Montréal, Montréal, QC, Canada
| | - Clémence Messmer
- Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Centre Affilié à l'Université de Montréal, Montréal, QC, Canada
| | - El Bachir Affar
- Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Centre Affilié à l'Université de Montréal, Montréal, QC, Canada
| | - Bruno Larrivée
- Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Centre Affilié à l'Université de Montréal, Montréal, QC, Canada
| | - Xue-Song Liu
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Casimiro Gerarduzzi
- Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada.
- Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Centre Affilié à l'Université de Montréal, Montréal, QC, Canada.
- Département de Médecine, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada.
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19
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Yost KE, Zhao Y, Hung KL, Zhu K, Xu D, Corces MR, Shams S, Louie BH, Sarmashghi S, Sundaram L, Luebeck J, Clarke S, Doane AS, Granja JM, Choudhry H, Imieliński M, Cherniack AD, Khurana E, Bafna V, Felau I, Zenklusen JC, Laird PW, Curtis C, Greenleaf WJ, Chang HY. Three-dimensional genome landscape of primary human cancers. Nat Genet 2025; 57:1189-1200. [PMID: 40355593 DOI: 10.1038/s41588-025-02188-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 04/02/2025] [Indexed: 05/14/2025]
Abstract
Genome conformation underlies transcriptional regulation by distal enhancers, and genomic rearrangements in cancer can alter critical regulatory interactions. Here we profiled the three-dimensional genome architecture and enhancer connectome of 69 tumor samples spanning 15 primary human cancer types from The Cancer Genome Atlas. We discovered the following three archetypes of enhancer usage for over 100 oncogenes across human cancers: static, selective gain or dynamic rewiring. Integrative analyses revealed the enhancer landscape of noncancer cells in the tumor microenvironment for genes related to immune escape. Deep whole-genome sequencing and enhancer connectome mapping provided accurate detection and validation of diverse structural variants across cancer genomes and revealed distinct enhancer rewiring consequences from noncoding point mutations, genomic inversions, translocations and focal amplifications. Extrachromosomal DNA promoted more extensive enhancer rewiring among several types of focal amplification mechanisms. These results suggest a systematic approach to understanding genome topology in cancer etiology and therapy.
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Affiliation(s)
- Kathryn E Yost
- Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA
- Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA
- Whitehead Institute for Biomedical Research, Cambridge, MA, USA
| | - Yanding Zhao
- Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA
- Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - King L Hung
- Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA
- Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Kaiyuan Zhu
- Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA
| | - Duo Xu
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York City, NY, USA
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York City, NY, USA
- Pathos AI, Chicago, IL, USA
| | - M Ryan Corces
- Gladstone Institute of Neurological Disease, San Francisco, CA, USA
- Gladstone Institute of Data Science and Biotechnology, San Francisco, CA, USA
- Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
| | - Shadi Shams
- Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA
- Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Bryan H Louie
- Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA
- Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA
| | | | - Laksshman Sundaram
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
- Department of Computer Science, Stanford University, Stanford, CA, USA
- Illumina AI laboratory, Illumina Inc, Foster City, CA, USA
- NVIDIA Bio Research, NVIDIA, Santa Clara, CA, USA
| | - Jens Luebeck
- Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA
| | - Stanley Clarke
- Vilcek Institute of Graduate Biomedical Sciences, NYU Grossman School of Medicine, New York City, NY, USA
- Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York City, NY, USA
- Department of Pathology, New York University Langone Health, New York City, NY, USA
- New York Genome Center, New York City, NY, USA
| | - Ashley S Doane
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York City, NY, USA
| | - Jeffrey M Granja
- Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA
- Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Hani Choudhry
- Department of Biochemistry, Faculty of Science, Cancer and Mutagenesis Unit, King Fahd Center for Medical Research, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Marcin Imieliński
- Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York City, NY, USA
- Department of Pathology, New York University Langone Health, New York City, NY, USA
- New York Genome Center, New York City, NY, USA
| | - Andrew D Cherniack
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Ekta Khurana
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York City, NY, USA
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York City, NY, USA
- Institute for Computational Biomedicine, Weill Cornell Medicine, New York City, NY, USA
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, NY, USA
| | - Vineet Bafna
- Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA
| | - Ina Felau
- National Cancer Institute, NIH, Bethesda, MD, USA
| | | | - Peter W Laird
- Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI, USA
| | - Christina Curtis
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Chan Zuckerberg Biohub, San Francisco, CA, USA
| | - William J Greenleaf
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Applied Physics, Stanford University, Stanford, CA, USA.
| | - Howard Y Chang
- Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.
- Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
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20
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Wang J, Ye F, Chai H, Jiang Y, Wang T, Ran X, Xia Q, Xu Z, Fu Y, Zhang G, Wu H, Guo G, Guo H, Ruan Y, Wang Y, Xing D, Xu X, Zhang Z. Advances and applications in single-cell and spatial genomics. SCIENCE CHINA. LIFE SCIENCES 2025; 68:1226-1282. [PMID: 39792333 DOI: 10.1007/s11427-024-2770-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 10/10/2024] [Indexed: 01/12/2025]
Abstract
The applications of single-cell and spatial technologies in recent times have revolutionized the present understanding of cellular states and the cellular heterogeneity inherent in complex biological systems. These advancements offer unprecedented resolution in the examination of the functional genomics of individual cells and their spatial context within tissues. In this review, we have comprehensively discussed the historical development and recent progress in the field of single-cell and spatial genomics. We have reviewed the breakthroughs in single-cell multi-omics technologies, spatial genomics methods, and the computational strategies employed toward the analyses of single-cell atlas data. Furthermore, we have highlighted the advances made in constructing cellular atlases and their clinical applications, particularly in the context of disease. Finally, we have discussed the emerging trends, challenges, and opportunities in this rapidly evolving field.
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Affiliation(s)
- Jingjing Wang
- Bone Marrow Transplantation Center of the First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Fang Ye
- Bone Marrow Transplantation Center of the First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Haoxi Chai
- Life Sciences Institute and The Second Affiliated Hospital, Zhejiang University, Hangzhou, 310058, China
| | - Yujia Jiang
- BGI Research, Shenzhen, 518083, China
- BGI Research, Hangzhou, 310030, China
| | - Teng Wang
- Biomedical Pioneering Innovation Center (BIOPIC) and School of Life Sciences, Peking University, Beijing, 100871, China
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China
| | - Xia Ran
- Bone Marrow Transplantation Center of the First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, 310058, China
- Institute of Hematology, Zhejiang University, Hangzhou, 310000, China
| | - Qimin Xia
- Biomedical Pioneering Innovation Center (BIOPIC) and School of Life Sciences, Peking University, Beijing, 100871, China
| | - Ziye Xu
- Department of Laboratory Medicine of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Yuting Fu
- Bone Marrow Transplantation Center of the First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, 310058, China
- Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Guodong Zhang
- Bone Marrow Transplantation Center of the First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, 310058, China
- Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Hanyu Wu
- Bone Marrow Transplantation Center of the First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, 310058, China
- Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Guoji Guo
- Bone Marrow Transplantation Center of the First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, 310058, China.
- Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China.
- Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Hangzhou, 310058, China.
- Institute of Hematology, Zhejiang University, Hangzhou, 310000, China.
| | - Hongshan Guo
- Bone Marrow Transplantation Center of the First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, 310058, China.
- Institute of Hematology, Zhejiang University, Hangzhou, 310000, China.
| | - Yijun Ruan
- Life Sciences Institute and The Second Affiliated Hospital, Zhejiang University, Hangzhou, 310058, China.
| | - Yongcheng Wang
- Department of Laboratory Medicine of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, 310058, China.
| | - Dong Xing
- Biomedical Pioneering Innovation Center (BIOPIC) and School of Life Sciences, Peking University, Beijing, 100871, China.
- Beijing Advanced Innovation Center for Genomics (ICG), Peking University, Beijing, 100871, China.
| | - Xun Xu
- BGI Research, Shenzhen, 518083, China.
- BGI Research, Hangzhou, 310030, China.
- Guangdong Provincial Key Laboratory of Genome Read and Write, BGI Research, Shenzhen, 518083, China.
| | - Zemin Zhang
- Biomedical Pioneering Innovation Center (BIOPIC) and School of Life Sciences, Peking University, Beijing, 100871, China.
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21
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Choudalakis S, Kastis GA, Dikaios N. Intra-clustering analysis reveals tissue-specific mutational patterns. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2025; 263:108681. [PMID: 40050208 DOI: 10.1016/j.cmpb.2025.108681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 02/06/2025] [Accepted: 02/18/2025] [Indexed: 03/14/2025]
Abstract
BACKGROUND AND OBJECTIVE The identification of tissue-specific mutational patterns associated with cancer is challenging due to the low frequency of certain mutations and the high variability among tumors within the same cancer type. To address the inter-tumoral heterogeneity issue, our study aims to uncover infrequent mutational patterns by proposing a novel intra-clustering analysis. METHODS A Network Graph of 8303 patients and 198 genes was constructed using single-point-mutation data from The Cancer Genome Atlas (TCGA). Patient-gene groups were retrieved with the parallel use of two separate methodologies based on the: (a) Barber's modularity index, and (b) network dynamics. An intra-clustering analysis was employed to explore the patterns within smaller patient subgroups in two phases: i) to determine the significant presence of a gene with a cancer type using the Fisher's exact test and ii) to determine gene-to-gene patterns using multiple correspondence analysis and DISCOVER. The results are followed by a Benjamini-Hochberg false discovery rate of 5%. RESULTS This analysis was applied over 24 statistically meaningful groups of 2619 patients spanning 21 cancer types and it recovered 42 mutational patterns that are not reported in the TCGA consortium publications. Notably, our findings: (i) suggest that AMER1 mutations are a putative separative element between colon and rectal adenocarcinomas, (ii) highlight the significant presence of RAC1 in head and neck squamous cell carcinoma (iii) suggest that EP300 mutations in head and neck squamous cell carcinoma are irrelevant of the HPV status of the patients and (iv) show that mutational-based clusters can contain patients with contrasting genetic alterations. CONCLUSIONS The proposed intra-clustering analysis extracted statistically significant relationships within clusters, uncovering putative clinically relevant connections and disentangling mutational heterogeneity.
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Affiliation(s)
- Stamatis Choudalakis
- Mathematics Research Center, Academy of Athens, 4, Soranou Efesiou str., 11527 Athens, Greece; Medical School of Athens, National and Kapodistrian University of Athens, 75, Mikras Asias str., 11527 Athens, Greece.
| | - George A Kastis
- Mathematics Research Center, Academy of Athens, 4, Soranou Efesiou str., 11527 Athens, Greece.
| | - Nikolaos Dikaios
- Mathematics Research Center, Academy of Athens, 4, Soranou Efesiou str., 11527 Athens, Greece.
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22
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Finger AM, Hendley AM, Figueroa D, Gonzalez H, Weaver VM. Tissue mechanics in tumor heterogeneity and aggression. Trends Cancer 2025:S2405-8033(25)00096-2. [PMID: 40307158 DOI: 10.1016/j.trecan.2025.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 03/10/2025] [Accepted: 04/04/2025] [Indexed: 05/02/2025]
Abstract
Tumorigenesis ensues within a heterogeneous tissue microenvironment that promotes malignant transformation, metastasis and treatment resistance. A major feature of the tumor microenvironment is the heterogeneous population of cancer-associated fibroblasts and myeloid cells that stiffen the extracellular matrix. The heterogeneously stiffened extracellular matrix in turn activates cellular mechanotransduction and creates a hypoxic and metabolically hostile microenvironment. The stiffened extracellular matrix and elevated mechanosignaling also drive tumor aggression by fostering tumor cell growth, survival, and invasion, compromising antitumor immunity, expanding cancer stem cell frequency, and increasing mutational burden, which promote intratumor heterogeneity. Delineating the molecular mechanisms whereby tissue mechanics regulate these phenotypes should help to clarify the basis for tumor heterogeneity and cancer aggression and identify novel therapeutic targets that could improve patient outcome. Here, we discuss the role of the extracellular matrix in driving cancer aggression through its impact on tumor heterogeneity.
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Affiliation(s)
- Anna-Marie Finger
- Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA 94143; Current address: Liver Disease Research, Global Drug Discovery, Novo Nordisk A/S, Malov, Denmark
| | - Audrey Marie Hendley
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA 94143
| | - Diego Figueroa
- Department of Radiation Oncology, Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA
| | - Hugo Gonzalez
- Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA 94143; Current address: Laboratory of Tumor Microenvironment and Metastasis, Centro Ciencia & Vida, Santiago, Chile
| | - Valerie Marie Weaver
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA 94143; Department of Radiation Oncology, Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA.
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23
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Kyuno D, Asano H, Okumura R, Takasawa K, Takasawa A, Konno T, Nakamori Y, Magara K, Ono Y, Imamura M, Kimura Y, Kojima T, Osanai M. The Role of Claudin-1 in Enhancing Pancreatic Cancer Aggressiveness and Drug Resistance via Metabolic Pathway Modulation. Cancers (Basel) 2025; 17:1469. [PMID: 40361399 PMCID: PMC12070999 DOI: 10.3390/cancers17091469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2025] [Revised: 04/17/2025] [Accepted: 04/24/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND/OBJECTIVES Pancreatic ductal adenocarcinoma is a lethal malignancy, necessitating an understanding of its molecular mechanisms for the development of new therapeutic strategies. The tight junction protein claudin-1, known to influence cellular functions in various cancers and is considered a therapeutic target, remains unclear in pancreatic cancer. METHODS This study assessed claudin-1 expression in resected pancreatic cancer samples, public databases, and pancreatic cancer cell lines. Claudin-1 knockout with CRISPR/Cas9 on poorly differentiated pancreatic cancer cell lines and a proteome analysis were performed to investigate the intracellular mechanisms of claudin-1. RESULTS Claudin-1 was markedly overexpressed in pancreatic ductal adenocarcinoma and intraepithelial neoplasia compared to normal ducts, and high claudin-1 levels were an independent predictor of poor prognosis. Claudin-1 knockout diminished cell proliferation, migration, invasion, and chemoresistance in pancreatic ductal adenocarcinoma. Proteome analysis revealed the significant downregulation of aldo-keto reductase family proteins (AKR1C2, AKR1C3, and AKR1B1) in claudin-1 knockout cells, which are linked to metabolic pathways. Aldo-keto reductase knockdown reduced chemoresistance, proliferation, and invasion in these cell lines. CONCLUSIONS These findings indicate that the abnormal expression of claudin-1 promotes tumor progression and drug resistance through its interaction with aldo-keto reductase proteins, highlighting claudin-1 and aldo-keto reductase family proteins as potential biomarkers and therapeutic targets for pancreatic cancer.
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Affiliation(s)
- Daisuke Kyuno
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
- Department of Surgery, Division of Gastroenterological Surgery, Sapporo Medical University, Sapporo 060-8556, Japan
| | - Hinae Asano
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
| | - Reona Okumura
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
| | - Kumi Takasawa
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa 078-8510, Japan
| | - Akira Takasawa
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa 078-8510, Japan
| | - Takumi Konno
- Department of Cell Science, Institute of Cancer Research, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
| | - Yuna Nakamori
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
| | - Kazufumi Magara
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
| | - Yusuke Ono
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
| | - Masafumi Imamura
- Department of Surgery, Division of Gastroenterological Surgery, Sapporo Medical University, Sapporo 060-8556, Japan
| | - Yasutoshi Kimura
- Department of Surgery, Division of Gastroenterological Surgery, Sapporo Medical University, Sapporo 060-8556, Japan
| | - Takashi Kojima
- Department of Cell Science, Institute of Cancer Research, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
| | - Makoto Osanai
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
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24
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Emmerich PB, Qyli T, Johnson KA, Chaudhuri S, Clark KM, Verhagen NB, Depke MG, Clipson L, Pasch CA, Papadas A, Burkard ME, Wisinski KB, McGregor SM, Asimakopoulos F, Deming DA. Stromal Versican Accumulation and Proteolysis Regulate the Infiltration of CD8 + T Cells in Breast Cancer. Cancers (Basel) 2025; 17:1435. [PMID: 40361362 PMCID: PMC12070914 DOI: 10.3390/cancers17091435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 03/28/2025] [Accepted: 04/18/2025] [Indexed: 05/15/2025] Open
Abstract
Background/Objectives: Recent clinical trials in breast cancer have demonstrated that some patients benefit from immune checkpoint blockade, though better predictive markers are needed. The accumulation of the immunomodulatory matrix proteoglycan versican (VCAN) can predict the exclusion of CD8+ tumor-infiltrating lymphocytes (TILs) in some settings and, thus, is evaluated in breast cancer here. Methods: A total of 230 breast cancers were analyzed for VCAN accumulation, VCAN proteolysis, and CD8+ TILs. CD8+ TILs were categorized based on their localization in the tumor epithelial or stromal compartments. Results: VCAN accumulation was detected in 90% of breast cancers, more commonly in ER+ tumors (93% vs. 77%; p < 0.001). MCF7 cells treated with estrogen upregulate VCAN without an enhanced expression of ADAMTS-proteases. VCAN-undetectable tumors demonstrate greater CD8+ TILs compared to VCAN-detectable tumors (p = 0.012). CD8+ T cells within TNBC tumors with high VCAN proteolysis infiltrated the epithelial compartment more often than in tumors with low VCAN proteolysis (91% vs. 42% respectively; p = 0.008). In the TCGA cohort, a strong inverse correlation between CD8A and VCAN expression was observed across subtypes. Conclusions: VCAN accumulation correlates with the exclusion of CD8+ TILs across subtypes of breast cancer, warranting further validation of VCAN accumulation and proteolysis as predictive biomarkers for breast cancer immunotherapy.
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Affiliation(s)
- Philip B. Emmerich
- Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
- Cellular and Molecular Pathology Graduate Program, Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Tonela Qyli
- Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Katherine A. Johnson
- Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Somak Chaudhuri
- Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Kristen M. Clark
- Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Nathaniel B. Verhagen
- Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Mitchell G. Depke
- Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Linda Clipson
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Cheri A. Pasch
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Athanasios Papadas
- Cellular and Molecular Pathology Graduate Program, Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
- Division of Blood and Marrow Transplantation and Moores Cancer Center, University of California-San Diego, La Jolla, CA 92093, USA
| | - Mark E. Burkard
- Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Kari B. Wisinski
- Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Stephanie M. McGregor
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Fotis Asimakopoulos
- Division of Blood and Marrow Transplantation and Moores Cancer Center, University of California-San Diego, La Jolla, CA 92093, USA
| | - Dustin A. Deming
- Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA
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25
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Yan Y, Wang Y, Tang J, Liu X, Wang J, Song G, Li H. Comprehensive Analysis of Oncogenic Somatic Alterations of Mismatch Repair Gene in Breast Cancer Patients. Bioengineering (Basel) 2025; 12:426. [PMID: 40281786 PMCID: PMC12025084 DOI: 10.3390/bioengineering12040426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 03/12/2025] [Accepted: 03/19/2025] [Indexed: 04/29/2025] Open
Abstract
Recent clinical trials have suggested that solid cancers with mismatch repair (MMR) deficiency are highly responsive to immunotherapy, regardless of cancer types. Previous MMR-related studies on breast cancer have predominantly focused on germline variants. However, the somatic MMR alterations have not been comprehensively characterized in breast cancer. In this study, we integrated genomic, transcriptomic, and clinical data from over 3000 breast cancer cases across six public cohorts. Our findings revealed that 1.2% of breast cancers harbored oncogenic somatic MMR alterations, with triple-negative breast cancer (TNBC) demonstrating the highest mutation rate at 3.1%. Additionally, somatic MMR alterations were significantly associated with microsatellite instability-high (MSI-H) and MMR-related mutational signatures, indicating that somatic MMR alterations led to impaired function of the MMR system. Biallelic inactivation of MMR genes resulted in a more pronounced loss of MMR function compared to monoallelic inactivation. Importantly, these MMR alterations significantly increased the tumor mutational burden (TMB) and neoantigen load in breast cancer, regardless of MSI-H status. These findings indicate that the frequency of MMR alterations is highest in TNBC and that MMR alterations in breast cancer can lead to MMR functional deficiencies, suggesting that some patients harboring such alterations may benefit from immunotherapy.
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Affiliation(s)
- Yin Yan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China; (Y.Y.); (X.L.)
| | - Yang Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Comprehensive Clinical Trial Ward, Peking University Cancer Hospital & Institute, Beijing 100142, China;
| | - Junjie Tang
- The First Clinical Medical School, Nanjing Medical University, Nanjing 211166, China;
| | - Xiaoran Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China; (Y.Y.); (X.L.)
| | - Jichuan Wang
- Musculoskleletal Tumor Center, Beijing Key Laboratory for Musculoskeletal Tumors, Peking University People’s Hospital, Beijing 100041, China;
| | - Guohong Song
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China; (Y.Y.); (X.L.)
| | - Huiping Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China; (Y.Y.); (X.L.)
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26
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Pepe G, Notturno Granieri C, Appierdo R, Ausiello G, Helmer-Citterich M, Gherardini PF. PANDA: PAN Cancer Data Analysis Web Tool. J Mol Biol 2025:169158. [PMID: 40250704 DOI: 10.1016/j.jmb.2025.169158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 03/05/2025] [Accepted: 04/10/2025] [Indexed: 04/20/2025]
Abstract
Cancer research faces challenges due to the genetic diversity within tumors and individual variability. Precision medicine aims to identify genomic and molecular factors linked to clinical outcomes, leveraging large datasets for drug discovery and patient stratification. We introduce PANDA (PAN-cancer Data Analysis web tool) (https://panda.bio.uniroma2.it), a web server designed for analyzing TCGA genomic data. A total of 32 tumor types and 10,711 samples were selected for this analysis. PANDA simplifies complex tasks such as differential expression, survival analysis, and patient stratification, incorporating clinical factors like sex, stage, and treatment history. It also enables the exploration of biological pathways and immune cell type proportion, providing insights into tumor progression. PANDA is user-friendly, designed for researchers with limited informatics expertise, and supports diverse analyses to advance cancer research.
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Affiliation(s)
- G Pepe
- Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 1, 00133 Rome, Italy.
| | - C Notturno Granieri
- Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 1, 00133 Rome, Italy
| | - R Appierdo
- Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 1, 00133 Rome, Italy; PhD Program in Cellular and Molecular Biology, Department of Biology, University of Rome "Tor Vergata", Rome, Italy
| | - G Ausiello
- Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 1, 00133 Rome, Italy
| | - M Helmer-Citterich
- Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 1, 00133 Rome, Italy.
| | - P F Gherardini
- Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 1, 00133 Rome, Italy.
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27
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Espinoza-Ferrao S, Echeverría-Garcés G, Rivera-Orellana S, Bueno-Miño J, Castellanos-Molina E, Benítez-Núñez M, López-Cortés A. Global analysis of actionable genomic alterations in thyroid cancer and precision-based pharmacogenomic strategies. Front Pharmacol 2025; 16:1524623. [PMID: 40297138 PMCID: PMC12034932 DOI: 10.3389/fphar.2025.1524623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 04/01/2025] [Indexed: 04/30/2025] Open
Abstract
Introduction Thyroid cancer, a prevalent endocrine malignancy, has an age-standardized incidence rate of 9.1 per 100,000 people and a mortality rate of 0.44 per 100,000 as of 2024. Despite significant advances in precision oncology driven by large-scale international consortia, gaps persist in understanding the genomic landscape of thyroid cancer and its impact on therapeutic efficacy across diverse populations. Methods To address this gap, we performed comprehensive data mining and in silico analyses to identify pathogenic variants in thyroid cancer driver genes, calculate allele frequencies, and assess deleteriousness scores across global populations, including African, Amish, Ashkenazi Jewish, East and South Asian, Finnish and non-Finnish European, Latino, and Middle Eastern groups. Additionally, pharmacogenomic profiling, in silico drug prescription, and clinical trial data were analyzed to prioritize targeted therapeutic strategies. Results Our analysis examined 56,622 variants in 40 thyroid cancer-driver genes across 76,156 human genomes, identifying 5,001 known and predicted oncogenic variants. Enrichment analysis revealed critical pathways such as MAPK, PI3K-AKT-mTOR, and p53 signaling, underscoring their roles in thyroid cancer pathogenesis. High-throughput validation strategies confirmed actionable genomic alterations in RET, BRAF, NRAS, KRAS, and EPHA7. Ligandability assessments identified these proteins as promising therapeutic targets. Furthermore, our findings highlight the clinical potential of targeted drug inhibitors, including vandetanib, dabrafenib, and selumetinib, for improving treatment outcomes. Discussion This study underscores the significance of integrating genomic insights with pharmacogenomic strategies to address disparities in thyroid cancer treatment. The identification of population-specific oncogenic variants and actionable therapeutic targets provides a foundation for advancing precision oncology. Future efforts should focus on including underrepresented populations, developing population-specific prevention strategies, and fostering global collaboration to ensure equitable access to pharmacogenomic testing and innovative therapies. These initiatives have the potential to transform thyroid cancer care and align with the broader goals of personalized medicine.
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Affiliation(s)
| | - Gabriela Echeverría-Garcés
- Centro de Referencia Nacional de Genómica, Secuenciación y Bioinformática, Instituto Nacional de Investigación en Salud Pública “Leopoldo Izquieta Pérez”, Quito, Ecuador
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago, Chile
| | | | - José Bueno-Miño
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| | | | - Melanie Benítez-Núñez
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| | - Andrés López-Cortés
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
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28
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Chen LT, Jager M, Rebergen D, Brink GJ, van den Ende T, Vanderlinden W, Kolbeck P, Pagès-Gallego M, van der Pol Y, Besselink N, Moldovan N, Hami N, Kloosterman WP, van Laarhoven H, Mouliere F, Zweemer R, Lipfert J, Derks S, Marcozzi A, de Ridder J. Nanopore-based consensus sequencing enables accurate multimodal tumor cell-free DNA profiling. Genome Res 2025; 35:886-899. [PMID: 39805703 PMCID: PMC12047234 DOI: 10.1101/gr.279144.124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 01/06/2025] [Indexed: 01/16/2025]
Abstract
Shallow genome-wide cell-free DNA sequencing holds great promise for noninvasive cancer monitoring by providing reliable copy number alteration (CNA) and fragmentomic profiles. Single-nucleotide variations (SNVs) are, however, much harder to identify with low sequencing depth due to sequencing errors. Here, we present Nanopore Rolling Circle Amplification (RCA)-enhanced Consensus Sequencing (NanoRCS), which leverages RCA and consensus calling based on genome-wide long-read nanopore sequencing to enable simultaneous multimodal tumor fraction (TF) estimation through SNVs, CNAs, and fragmentomics. The efficacy of NanoRCS is tested on 18 cancer patient samples and seven healthy controls, demonstrating its ability to reliably detect TFs as low as 0.24%. In vitro experiments confirm that SNV measurements are essential for detecting TFs below 3%. NanoRCS provides an opportunity for cost-effective and rapid sample processing, which aligns well with clinical needs, particularly in settings where quick and accurate cancer monitoring is essential for personalized treatment strategies.
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Affiliation(s)
- Li-Ting Chen
- Center for Molecular Medicine University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands
- Oncode Institute, 3521 AL Utrecht, The Netherlands
| | - Myrthe Jager
- Center for Molecular Medicine University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands
- Oncode Institute, 3521 AL Utrecht, The Netherlands
| | | | - Geertruid J Brink
- Department of Gynecologic Oncology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands
| | - Tom van den Ende
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Imaging and Biomarkers, 1105 AZ, Amsterdam, The Netherlands
| | - Willem Vanderlinden
- Soft Condensed Matter and Biophysics, Department of Physics and Debye Institute for Nanomaterials Science, Utrecht University, 3584 CC Utrecht, The Netherlands
- School of Physics and Astronomy, University of Edinburgh, EH9 3FD Edinburgh, United Kingdom
| | - Pauline Kolbeck
- Soft Condensed Matter and Biophysics, Department of Physics and Debye Institute for Nanomaterials Science, Utrecht University, 3584 CC Utrecht, The Netherlands
- Department of Physics and Center for NanoScience, LMU Munich, 80799 Munich, Germany
| | - Marc Pagès-Gallego
- Center for Molecular Medicine University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands
- Oncode Institute, 3521 AL Utrecht, The Netherlands
| | - Ymke van der Pol
- Department of Pathology, Cancer Centre Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, 1105 AZ, Amsterdam, The Netherlands
| | - Nicolle Besselink
- Center for Molecular Medicine University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands
- Oncode Institute, 3521 AL Utrecht, The Netherlands
| | - Norbert Moldovan
- Cancer Center Amsterdam, Imaging and Biomarkers, 1105 AZ, Amsterdam, The Netherlands
- Department of Pathology, Cancer Centre Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, 1105 AZ, Amsterdam, The Netherlands
| | - Nizar Hami
- Department of Gynecologic Oncology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands
| | | | - Hanneke van Laarhoven
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Imaging and Biomarkers, 1105 AZ, Amsterdam, The Netherlands
| | - Florent Mouliere
- Cancer Center Amsterdam, Imaging and Biomarkers, 1105 AZ, Amsterdam, The Netherlands
- Department of Pathology, Cancer Centre Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, 1105 AZ, Amsterdam, The Netherlands
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, United Kingdom
| | - Ronald Zweemer
- Department of Gynecologic Oncology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands
| | - Jan Lipfert
- Soft Condensed Matter and Biophysics, Department of Physics and Debye Institute for Nanomaterials Science, Utrecht University, 3584 CC Utrecht, The Netherlands
| | - Sarah Derks
- Oncode Institute, 3521 AL Utrecht, The Netherlands
- Department of Pathology, Cancer Centre Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, 1105 AZ, Amsterdam, The Netherlands
| | | | - Jeroen de Ridder
- Center for Molecular Medicine University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands;
- Oncode Institute, 3521 AL Utrecht, The Netherlands
- Cyclomics, 3584 CG Utrecht, The Netherlands
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29
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Lv X, Liu J, Islam K, Ruan J, He C, Chen P, Huang C, Wang H, Dhar A, Moness M, Shi D, Murphy S, Zhao X, Yang S, Montoute I, Polakkattil A, Chung A, Ruiz E, Carbajal B, Padavala A, Chen L, Hua G, Chen X, Davis JS, Wang C. Hyperactivated YAP1 is essential for sustainable progression of renal clear cell carcinoma. Oncogene 2025:10.1038/s41388-025-03354-8. [PMID: 40210757 DOI: 10.1038/s41388-025-03354-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 02/12/2025] [Accepted: 03/17/2025] [Indexed: 04/12/2025]
Abstract
The most notable progress in renal clear cell carcinoma (ccRCC) in the past decades is the introduction of drugs targeting the VHL-HIF signaling pathway-associated angiogenesis. However, mechanisms underlying the development of VHL mutation-independent ccRCC are unclear. Here we provide evidence that the disrupted Hippo-YAP signaling contributes to the development of ccRCC independent of VHL alteration. We found that YAP1 and its primary target genes are frequently upregulated in ccRCC and the upregulation of these genes is associated with unfavorable patient outcomes. Research results derived from our in vitro and in vivo experimental models demonstrated that, under normoxic conditions, hyperactivated YAP1 drives the expression of FGFs to stimulate the proliferation of tumor and tumor-associated endothelial cells in an autocrine/paracrine manner. When rapidly growing cancer cells create a hypoxic environment, hyperactivated YAP1 in cancer cells induces the production of VEGF, which promotes the angiogenesis of tumor-associated endothelial cells, leading to improved tumor microenvironment and continuous tumor growth. Our study indicates that hyperactivated YAP1 is essential for maintaining ccRCC progression, and targeting the dual role of hyperactivated YAP1 represents a novel strategy to improve renal carcinoma therapy.
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Affiliation(s)
- Xiangmin Lv
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jiyuan Liu
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Kazi Islam
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jinpeng Ruan
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Chunbo He
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Department of Obstetrics and Gynecology, Olson Center for Women's Health, University of Nebraska Medical Center, Omaha, NE, USA
| | - Peichao Chen
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Cong Huang
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Hongbo Wang
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Anjali Dhar
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Department of Chemistry, Dartmouth College, Hanover, NH, USA
| | - Madelyn Moness
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Davie Shi
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Department of Neurobiology, Northwestern University, Evanston, IL, USA
| | - Savannah Murphy
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Xingeng Zhao
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Siyi Yang
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Isabelle Montoute
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA
| | - Aneeta Polakkattil
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Andie Chung
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Emily Ruiz
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA
| | - Brianna Carbajal
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Department of Stem cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Alekhya Padavala
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Li Chen
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Guohua Hua
- Department of Obstetrics and Gynecology, Olson Center for Women's Health, University of Nebraska Medical Center, Omaha, NE, USA
| | - Xingcheng Chen
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - John S Davis
- Department of Obstetrics and Gynecology, Olson Center for Women's Health, University of Nebraska Medical Center, Omaha, NE, USA
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
- Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA
| | - Cheng Wang
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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30
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Vivalda F, Gatti M, Manfredi L, Dogan H, Porro A, Collotta G, Ceppi I, von Aesch C, van Ackeren V, Wild S, Steger M, Canovas B, Cubillos-Rojas M, Riera A, Cejka P, Nebreda A, Dibitetto D, Rottenberg S, Sartori A. The PIN1-p38-CtIP signalling axis protects stalled replication forks from deleterious degradation. Nucleic Acids Res 2025; 53:gkaf278. [PMID: 40207632 PMCID: PMC11983131 DOI: 10.1093/nar/gkaf278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 03/20/2025] [Accepted: 03/26/2025] [Indexed: 04/11/2025] Open
Abstract
Human CtIP plays a critical role in homologous recombination (HR) by promoting the resection of DNA double-strand breaks. Moreover, CtIP maintains genome stability through protecting stalled replication forks from nucleolytic degradation. However, the upstream signalling mechanisms governing the molecular switch between these two CtIP-dependent processes remain largely elusive. Here, we show that phosphorylation of CtIP by the p38α stress kinase and subsequent PIN1-mediated CtIP cis-to-trans isomerization is required for fork stabilization but dispensable for HR. We found that stalled forks are degraded in cells expressing non-phosphorylatable CtIP or lacking PIN1-p38α activity, while expression of a CtIP trans-locked mutant overcomes the requirement for PIN1-p38α in fork protection. We further reveal that Brca1-deficient mammary tumour cells that have acquired PARP inhibitor (PARPi) resistance regain chemosensitivity after PIN1 or p38α inhibition. Collectively, our findings identify the PIN1-p38-CtIP signalling pathway as a critical regulator of replication fork integrity.
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Affiliation(s)
- Francesca Vivalda
- Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland
| | - Marco Gatti
- Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland
| | - Letizia Manfredi
- Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland
| | - Hülya Dogan
- Institute of Animal Pathology and Bern Center for Precision Medicine, University of Bern, 3001 Bern, Switzerland
| | - Antonio Porro
- Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland
| | - Giulio Collotta
- Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland
| | - Ilaria Ceppi
- Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland
| | - Christine von Aesch
- Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland
| | - Vanessa van Ackeren
- Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland
| | - Sebastian Wild
- Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland
| | - Martin Steger
- NEOsphere Biotechnologies, 82152 Martinsried, Germany
| | - Begoña Canovas
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
| | - Monica Cubillos-Rojas
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
| | - Antoni Riera
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
- Departament de Química Inorgànica i Orgànica, Secció de Química Orgànica, Universitat de Barcelona, 08028 Barcelona, Spain
| | - Petr Cejka
- Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland
| | - Angel R Nebreda
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
- ICREA, 08010 Barcelona, Spain
| | - Diego Dibitetto
- Institute of Animal Pathology and Bern Center for Precision Medicine, University of Bern, 3001 Bern, Switzerland
- Department of Experimental Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
| | - Sven Rottenberg
- Institute of Animal Pathology and Bern Center for Precision Medicine, University of Bern, 3001 Bern, Switzerland
- Cancer Therapy Resistance Cluster, Department for Biomedical Research, University of Bern, 3008 Bern, Switzerland
| | - Alessandro A Sartori
- Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland
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31
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Bates BA, Bates KE, Boris SA, Wessman C, Stone D, Bryan J, Davis MF, Bailey MH. Intersection of rare pathogenic variants from TCGA in the All of Us Research Program v6. HGG ADVANCES 2025; 6:100405. [PMID: 39799398 PMCID: PMC11830373 DOI: 10.1016/j.xhgg.2025.100405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 01/09/2025] [Accepted: 01/08/2025] [Indexed: 01/15/2025] Open
Abstract
Using rare cancer predisposition alleles derived from The Cancer Genome Atlas (TCGA) and high cancer prevalence (14% of participants) in All of Us (version 6), we assessed the impact of these rare alleles on cancer occurrence in six broad groups of genetic similarity provided by All of Us: African/African American (AFR), Admixed American/Latino (AMR), East Asian (EAS), European (EUR), Middle Eastern (MID), or South Asian (SAS). We observed that germline susceptibility to cancer consistently replicates in EUR-like participants but less so in other participants. We found that All of Us participants from the EUR (p = 1.8 × 10-7), AFR (p = 0.018), and MID (p = 0.0083) genetic similarity groups who carry a rare pathogenic mutation are more likely to have cancer than those without a rare pathogenic mutation. With the advent of combining medical records and genetic mutations, we also performed a phenome-wide association study (PheWAS) to assess the effect of pathogenic variants on additional phenotypes. This analysis again showed several associations between predisposition variants and cancer in EUR-like participants, but fewer in those of the other genetic similarity groups. As All of Us grows to 1 million participants, our projections suggest sufficient power (>99%) to detect cancer-associated variants that are common, but limited power (∼28%) to detect rare mutations when using the entire cohort. This study provides preliminary insights into genetic predispositions to cancer across a diverse cohort and demonstrates the value of All of Us as a resource for cancer research.
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Affiliation(s)
- Blaine A Bates
- Department of Biology, Brigham Young University, Provo, UT 84061, USA; Department of Chemical Engineering, Brigham Young University, Provo, UT 84602, USA
| | - Kylee E Bates
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA
| | - Spencer A Boris
- Department of Biology, Brigham Young University, Provo, UT 84061, USA
| | - Colin Wessman
- Department of Biology, Brigham Young University, Provo, UT 84061, USA
| | - David Stone
- Department of Biology, Brigham Young University, Provo, UT 84061, USA
| | - Justin Bryan
- Department of Biology, Brigham Young University, Provo, UT 84061, USA
| | - Mary F Davis
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA; Department of Biomedical Informatics, Vanderbilt University, Nashville, TN 37203, USA
| | - Matthew H Bailey
- Department of Biology, Brigham Young University, Provo, UT 84061, USA; Simmons Center for Cancer Research, Brigham Young University, Provo, UT 84602, USA.
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Wala J, Dalin S, Webster S, Shapira O, Busanovich J, Sarmashghi S, Beroukhim R, Bandopadhayay P, Rendo V. Recurrent breakpoints in the BRD4 locus reduce toxicity associated with gene amplification. CELL GENOMICS 2025; 5:100815. [PMID: 40112818 PMCID: PMC12008804 DOI: 10.1016/j.xgen.2025.100815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 12/09/2024] [Accepted: 02/21/2025] [Indexed: 03/22/2025]
Abstract
Recent work by the ICGC-PCAWG consortium identified recurrent focal deletions in the BRD4 gene, decreasing expression despite increased copy number. We show that these focal deletions occur in the context of cyclin E1 amplification in breast, ovarian, and endometrial cancers, and serve to disrupt BRD4 regulatory regions and gene expression across isoforms. We analyze open reading frame screen data and find that overexpression of BRD4 long (BRD4-L) and short isoform BRD4-S(a) impairs cell growth across cell lines. We confirm these results in OVSAHO ovarian cancer cells, where the overexpression of BRD4 isoforms significantly reduces tumor growth. Next, we mimic BRD4 focal deletions using CRISPR-Cas9 technology and show that these focal deletions rescue ovarian cancer cells from toxicity associated with BRD4 overexpression, suggesting that BRD4 levels must be fine-tuned for cancer cell proliferation. Our study provides experimental evidence for the first recurrent deletion reducing toxicity in cancer, expanding the landscape of cancer progression mechanisms.
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Affiliation(s)
- Jeremiah Wala
- Departments of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Simona Dalin
- Departments of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Sophie Webster
- Departments of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Ofer Shapira
- Departments of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - John Busanovich
- Departments of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | | | - Rameen Beroukhim
- Departments of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Pratiti Bandopadhayay
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Veronica Rendo
- Departments of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Immunology, Genetics, and Pathology, Uppsala University, 75185 Uppsala, Sweden.
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Golas MM, Gunawan B, Gutenberg A, Danner BC, Gerdes JS, Stadelmann C, Füzesi L, Liersch T, Sander B. Cytogenetic signatures favoring metastatic organotropism in colorectal cancer. Nat Commun 2025; 16:3261. [PMID: 40188208 PMCID: PMC11972295 DOI: 10.1038/s41467-025-58413-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 03/21/2025] [Indexed: 04/07/2025] Open
Abstract
Colorectal carcinoma (CRC) exhibits metastatic organotropism, primarily targeting liver, lung, and rarely the brain. Here, we study chromosomal imbalances (CIs) in cohorts of primary CRCs and metastases. Brain metastases show the highest burden of CIs, including aneuploidies and focal CIs, with enrichment of +12p encoding KRAS. Compared to liver and lung metastases, brain metastases present with increased co-occurrence of KRAS mutation and amplification. CRCs with concurrent KRAS mutation and amplification display significant metabolic reprogramming with upregulation of glycolysis, alongside upregulation of cell cycle pathways, including copy number gains of MDM2 and CDK4. Evolutionary modeling suggests early acquisition of many organotropic CIs enriched in both liver and brain metastases, while brain-enriched CIs preferentially emerge later. Collectively, this study supports a model where cytogenetic events in CRCs favor site-specific metastatic colonization. These site-enriched CI patterns may serve as biomarkers for metastatic potential in precision oncology.
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Affiliation(s)
- Mariola Monika Golas
- Human Genetics, Faculty of Medicine, University of Augsburg, Augsburg, Germany.
- Comprehensive Cancer Center Augsburg, University Medical Center Augsburg, Augsburg, Germany.
| | - Bastian Gunawan
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
- Institute of Pathology Northern Hesse, Kassel, Germany
| | - Angelika Gutenberg
- Department of Neurosurgery, Asklepios Hospital Harburg, Hamburg, Germany
| | - Bernhard C Danner
- Department of Cardiac, Thoracic and Vascular Surgery, University Medical Center Göttingen, Göttingen, Germany
| | - Jan S Gerdes
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
- Epilepsy Center Hamburg, Evangelical Hospital Alsterdorf, Neurology and Epileptology, Hamburg, Germany
| | - Christine Stadelmann
- Department of Neuropathology, University Medical Center Göttingen, Göttingen, Germany
| | - Laszlo Füzesi
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | - Torsten Liersch
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
| | - Bjoern Sander
- Institute of Pathology, Hannover Medical School, Hannover, Germany.
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Kou Z, Zhu S, Zhu J, Wang S, Zheng Y, Zhou S, Si Z, Zhu H. Multi-omics analysis identifies DLX4 as a novel biomarker for diagnosis, prognosis, and immune infiltration: from pan-cancer to renal cancer. Discov Oncol 2025; 16:467. [PMID: 40186710 PMCID: PMC11972278 DOI: 10.1007/s12672-025-02258-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 03/28/2025] [Indexed: 04/07/2025] Open
Abstract
BACKGROUND DLX4 is involved in the regulation of embryonic development, but its function in cancer remains unclear. Here, we conducted a pan-cancer analysis to investigate the molecular mechanisms of DLX4, with a particular emphasis on its role in renal cancer. METHODS A comprehensive analysis of DLX4 was performed, focusing on differences in expression, prognostic value, somatic mutations, methylation modifications, and immune landscapes across various cancer types using multiple databases. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were utilized to explore the potential biological functions. Additionally, we evaluated the expression profile, prognostic significance, and immune infiltration of DLX4 in Kidney Renal Clear Cell Carcinoma (KIRC). The effect of DLX4 on KIRC was further validated by Spatial Transcriptomics, Real-time PCR (RT-PCR), and Immunohistochemistry experiments. RESULTS DLX4 was found to be upregulated in 26 cancer types and associated with poor prognosis. It was also correlated with tumor mutational burden (TMB), microsatellite instability, mismatch repair, and methylation, and was significantly enriched in pathways related to cell proliferation. In KIRC, DLX4 expression increased along with TMB and immune scores, likely due to the infiltration of regulatory T cells (Tregs) and T-helper 2 (Th2) cells. Spatial transcriptomics revealed a strong correlation between DLX4 localization and tumor cells. Experimental validation confirmed that DLX4 expression is significantly upregulated in renal cancer tissues. CONCLUSION Our study explored the mechanisms of DLX4 in pan-cancer, especially in renal clear cell carcinoma, identifying it as a promising biomarker and therapeutic target.
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Affiliation(s)
- Zengshun Kou
- Department of Urology, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China
- Qingdao Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
| | - Shuaizhi Zhu
- Department of Urology, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China
- Qingdao West Coast New Area District Hospital, Qingdao, China
| | - Jiaxi Zhu
- Faculty of Arts & Science, University of Toronto - St. George Campus, Toronto, Canada
| | - Shufei Wang
- College of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Yu Zheng
- Department of Urology, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China
| | - Shengjie Zhou
- Department of Urology, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China
- Qingdao Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
| | - Zi'ang Si
- Department of Urology, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China
- Qingdao Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
| | - Hai Zhu
- Department of Urology, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China.
- Qingdao Hospital, University of Health and Rehabilitation Sciences, Qingdao, China.
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Pulice JL, Meyerson M. Amplified dosage of the NKX2-1 lineage transcription factor controls its oncogenic role in lung adenocarcinoma. Mol Cell 2025; 85:1311-1329.e16. [PMID: 40139189 DOI: 10.1016/j.molcel.2025.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 12/17/2024] [Accepted: 03/03/2025] [Indexed: 03/29/2025]
Abstract
Amplification-mediated oncogene overexpression is a critical and widespread driver event in cancer, yet our understanding of how amplification and dosage mediate oncogene regulation is limited. Here, we find that the most significant focal amplification event in lung adenocarcinoma (LUAD) targets a lineage "super-enhancer" near the NKX2-1 lineage transcription factor. The NKX2-1 super-enhancer is targeted by focal and co-amplification with NKX2-1 and controls NKX2-1 expression and regulation. We find that NKX2-1 directly controls enhancer accessibility to drive a lineage-addicted state in LUAD. We precisely map the effects of NKX2-1 dosage modulation upon both overexpression and knockdown and identify both linear and non-linear regulation by NKX2-1 dosage. We find that NKX2-1 is a widespread dependency in LUAD cell lines and that NKX2-1 confers persistence to EGFR inhibitors. Our data suggest a defining role for dosage in the oncogenic regulation of amplified NKX2-1 and that amplified NKX2-1 lineage addiction defines LUAD tumors.
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Affiliation(s)
- John L Pulice
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Biological and Biomedical Sciences Program, Harvard University, Cambridge, MA, USA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Matthew Meyerson
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA.
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Llorente A, Arora GK, Murad R, Emerling BM. Phosphoinositide kinases in cancer: from molecular mechanisms to therapeutic opportunities. Nat Rev Cancer 2025:10.1038/s41568-025-00810-1. [PMID: 40181165 DOI: 10.1038/s41568-025-00810-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/28/2025] [Indexed: 04/05/2025]
Abstract
Phosphoinositide kinases, extending beyond the well-known phosphoinositide 3-kinase (PI3K), are key players in the dynamic and site-specific phosphorylation of lipid phosphoinositides. Unlike PI3Ks, phosphatidylinositol 4-kinases (PI4Ks) and phosphatidylinositol phosphate kinases (PIPKs) do not usually exhibit mutational alterations, but mostly show altered expression in tumours, orchestrating a broad spectrum of signalling, metabolic and immune processes, all of which are crucial in the pathogenesis of cancer. Dysregulation of PI4Ks and PIPKs has been associated with various malignancies, which has sparked considerable interest towards their therapeutic targeting. In this Review we summarize the current understanding of the lesser-studied phosphoinositide kinase families, PI4K and PIPK, focusing on their functions and relevance in cancer. In addition, we provide an overview of ongoing efforts driving the preclinical and clinical development of phosphoinositide kinase-targeting molecules.
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Affiliation(s)
- Alicia Llorente
- Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Gurpreet K Arora
- Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Rabi Murad
- Bioformatics Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Brooke M Emerling
- Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
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Cron KR, Sivan A, Aquino-Michaels K, Ziblat A, Higgs EF, Sweis RF, Tonea R, Lee S, Gajewski TF. PKCδ Germline Variants and Genetic Deletion in Mice Augment Antitumor Immunity through Regulation of Myeloid Cells. Cancer Immunol Res 2025; 13:547-559. [PMID: 39808445 DOI: 10.1158/2326-6066.cir-23-0999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 07/04/2024] [Accepted: 01/10/2025] [Indexed: 01/16/2025]
Abstract
Based on the notion that hypomorphic germline genetic variants are linked to autoimmune diseases, we reasoned that novel targets for cancer immunotherapy might be identified through germline variants associated with greater T-cell infiltration into tumors. Here, we report that while investigating germline polymorphisms associated with a tumor immune gene signature, we identified protein kinase C delta (PKCδ) as a candidate. Genetic deletion of Prkcd in mice resulted in improved endogenous antitumor immunity and increased efficacy of anti-PD-L1. Single-cell RNA sequencing revealed myeloid cell expression of Prkcd, and PKCδ deletion caused a shift in macrophage gene expression from an M2-like to an M1-like phenotype. Conditional deletion of Prkcd in myeloid cells recapitulated improved tumor control that was augmented further with anti-PD-L1. Analysis of clinical samples confirmed an association between PRKCD variants and M1/M2 phenotype, as well as between a PKCδ knockout-like gene signature and clinical benefit from anti-PD-1. Our results identify PKCδ as a candidate therapeutic target that modulates myeloid cell states.
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Affiliation(s)
- Kyle R Cron
- Department of Pathology, The University of Chicago, Chicago, Illinois
- Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Ayelet Sivan
- Department of Pathology, The University of Chicago, Chicago, Illinois
- Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Keston Aquino-Michaels
- Department of Pathology, The University of Chicago, Chicago, Illinois
- Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Andrea Ziblat
- Department of Pathology, The University of Chicago, Chicago, Illinois
- Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Emily F Higgs
- Department of Pathology, The University of Chicago, Chicago, Illinois
- Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Randy F Sweis
- Department of Pathology, The University of Chicago, Chicago, Illinois
- Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Ruxandra Tonea
- Department of Pathology, The University of Chicago, Chicago, Illinois
- Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Seoho Lee
- Department of Pathology, The University of Chicago, Chicago, Illinois
- Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Thomas F Gajewski
- Department of Pathology, The University of Chicago, Chicago, Illinois
- Department of Medicine, The University of Chicago, Chicago, Illinois
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38
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Somes LK, Lei JT, Yi X, Chamorro DF, Shafer P, Gad AZ, Dobrolecki LE, Madaras E, Ahmed N, Lewis MT, Zhang B, Hoyos V. ZP4: A novel target for CAR-T cell therapy in triple negative breast cancer. Mol Ther 2025; 33:1621-1641. [PMID: 39980195 PMCID: PMC11997509 DOI: 10.1016/j.ymthe.2025.02.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 01/24/2025] [Accepted: 02/17/2025] [Indexed: 02/22/2025] Open
Abstract
Triple-negative breast cancer (TNBC) remains one of the most challenging subtypes of breast cancer to treat due to a lack of effective targeted therapies. Chimeric antigen receptor (CAR)-T cells hold promise, but their efficacy in solid tumors is often limited by on-target/off-tumor toxicities. Through comprehensive bioinformatic analysis of public RNA and proteomic data, we identified zona pellucida glycoprotein 4 (ZP4) as a novel target for TNBC. ZP4 RNA and protein were detected in a subset of TNBC patient samples and patient-derived xenograft (PDX) models, with expression otherwise restricted to oocytes. We generated 89 ZP4-specific novel monoclonal antibodies and used the single-chain variable fragment (scFv) antigen binding domains from the top three candidates to engineer CAR constructs. ZP4 CAR-T cells demonstrated efficacy against ZP4-expressing TNBC cells and PDX models. Additionally, we found that variations in the scFv antigen binding domain significantly influence CAR-T cell function.
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Affiliation(s)
- Lauren K Somes
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Jonathan T Lei
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Xinpei Yi
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Diego F Chamorro
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA
| | - Paul Shafer
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ahmed Z Gad
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA
| | - Lacey E Dobrolecki
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Emily Madaras
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA
| | - Nabil Ahmed
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA
| | - Michael T Lewis
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Bing Zhang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Valentina Hoyos
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA
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Keller P, Dawood M, Chohan BS, Minhas FUAA. HistoKernel: Whole slide image level Maximum Mean Discrepancy kernels for pan-cancer predictive modelling. Med Image Anal 2025; 101:103491. [PMID: 39938344 DOI: 10.1016/j.media.2025.103491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 01/27/2025] [Accepted: 01/31/2025] [Indexed: 02/14/2025]
Abstract
In computational pathology, labels are typically available only at the whole slide image (WSI) or patient level, necessitating weakly supervised learning methods that aggregate patch-level features or predictions to produce WSI-level scores for clinically significant tasks such as cancer subtype classification or survival analysis. However, existing approaches lack a theoretically grounded framework to capture the holistic distributional differences between the patch sets within WSIs, limiting their ability to accurately and comprehensively model the underlying pathology. To address this limitation, we introduce HistoKernel, a novel WSI-level Maximum Mean Discrepancy (MMD) kernel designed to quantify distributional similarity between WSIs using their local feature representation. HistoKernel enables a wide range of applications, including classification, regression, retrieval, clustering, survival analysis, multimodal data integration, and visualization of large WSI datasets. Additionally, HistoKernel offers a novel perturbation-based method for patch-level explainability. Our analysis over large pan-cancer datasets shows that HistoKernel achieves performance that typically matches or exceeds existing state-of-the-art methods across diverse tasks, including WSI retrieval (n = 9324), drug sensitivity regression (n = 551), point mutation classification (n = 3419), and survival analysis (n = 2291). By pioneering the use of kernel-based methods for a diverse range of WSI-level predictive tasks, HistoKernel opens new avenues for computational pathology research especially in terms of rapid prototyping on large and complex computational pathology datasets. Code and interactive visualization are available at: https://histokernel.dcs.warwick.ac.uk/.
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Affiliation(s)
- Piotr Keller
- Tissue Image Analytics Centre, University of Warwick, Coventry, CV4 7AL, United Kingdom.
| | - Muhammad Dawood
- Tissue Image Analytics Centre, University of Warwick, Coventry, CV4 7AL, United Kingdom
| | - Brinder Singh Chohan
- Department of Cellular Pathology, Royal Derby Hospital, Derby, DE22 3NE, United Kingdom
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Blaszczyk MB, Boukhar SA, Zhou Z, Berim L, Ganesan S, Riedlinger GM. Occult collision tumor of the gastroesophageal junction comprising adenocarcinomas with distinct molecular profiles. Cancer Genet 2025; 292-293:27-34. [PMID: 39805155 DOI: 10.1016/j.cancergen.2025.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 12/30/2024] [Accepted: 01/03/2025] [Indexed: 01/16/2025]
Abstract
Collision tumors, characterized by the coexistence of two unique neoplasms in close approximation, are rare and pose diagnostic challenges. This is particularly true when the unique neoplasms are of the same histologic type. Here we report such a case where comprehensive tumor profiling by next generation sequencing (NGS) as well as immunohistochemistry revealed two independent adenocarcinomas comprising what was initially diagnosed as a single adenocarcinoma of the gastroesophageal (GEJ) junction. Biopsy of the esophageal portion of the GEJ mass showed a mismatch repair deficient tumor with loss of immunoreactivity for MLH1 and PMS2, while the biopsy taken from the gastric portion of the mass revealed a separate tumor with a discordant, non-overlapping, set of molecular alterations, including an EML4::ALK fusion, as well as intact MMR. This case illustrates one way in which NGS can reveal diagnoses such as collision tumor that are wholly unexpected based on clinical and histological grounds. Such diagnoses can have important implications for patient care, particularly in cases where there is discordance for targetable molecular alterations.
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Affiliation(s)
- Maryjka B Blaszczyk
- Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA; Department of Pathology and Laboratory Medicine, Oregon Health and Science University, Portland, OR, USA.
| | - Sarag A Boukhar
- Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Zhongren Zhou
- Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA; Rutgers Cancer Institute, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Lyudmyla Berim
- Rutgers Cancer Institute, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Shridar Ganesan
- Rutgers Cancer Institute, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA; Center for Molecular Oncology, NYU Langone Perlmutter Cancer Center, New York, NY, USA
| | - Gregory M Riedlinger
- Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA; Rutgers Cancer Institute, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
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Yang L, Feng Y, Liu X, Zhang Q, Liu Y, Zhang X, Li P, Chen D. DYNC2H1 mutation as a potential predictive biomarker for immune checkpoint inhibitor efficacy in NSCLC and melanoma. Invest New Drugs 2025; 43:199-213. [PMID: 39934438 DOI: 10.1007/s10637-024-01495-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 12/19/2024] [Indexed: 02/13/2025]
Abstract
Dynein cytoplasmic 2 heavy chain 1 (DYNC2H1) is reported to play a potential role in cancer immunotherapy. However, the association between DYNC2H1 mutation and the clinical benefit of immunotherapy in non-small cell lung cancer (NSCLC) and melanoma remains to be elucidated. We collected data from three public immune checkpoint inhibitor (ICI)-treated NSCLC cohorts (n = 137 in total) and seven ICI-treated melanoma cohorts (n = 418 in total) to explore the potential of DYNC2H1 mutation as a predictive biomarker. The clinical outcomes, including the objective response rate (ORR) and progression-free survival (PFS), of patients with DYNC2H1 mutations are significantly better than those of patients with wild-type DYNC2H1. Multivariate Cox regression analysis confirmed that DYNC2H1 mutation was an independent predictive factor for ICI efficacy in NSCLC and melanoma. In addition, DYNC2H1 mutation exhibited no prognostic value for NSCLC or melanoma. Tumour mutational burden (TMB) and tumour neoantigen burden (TNB) were significantly higher in patients with DYNC2H1 mutation than in those with wild-type DYNC2H1 in both NSCLC and melanoma cohort. The analysis of immune-related genes and immune cell enrichment revealed an association between DYNC2H1 mutation and increased immune infiltration, revealing a potential mechanism underlying the predictive role of DYNC2H1 mutation in immunotherapy efficacy. In conclusion, DYNC2H1 mutation serves as a predictive biomarker of ICI efficacy in NSCLC and melanoma.
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Affiliation(s)
- Lu Yang
- Department of Science and Technology, Nanjing Forestry University, Nanjing, 210037, China
| | - Yanlong Feng
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Xuewen Liu
- The State Key Laboratory of Neurology and Oncology Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing Simcere Medical Laboratory Science Co., Ltd, Nanjing, 210002, China
| | - Qin Zhang
- The State Key Laboratory of Neurology and Oncology Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing Simcere Medical Laboratory Science Co., Ltd, Nanjing, 210002, China
| | - Yaqin Liu
- The State Key Laboratory of Neurology and Oncology Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing Simcere Medical Laboratory Science Co., Ltd, Nanjing, 210002, China
| | - Xing Zhang
- The State Key Laboratory of Neurology and Oncology Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing Simcere Medical Laboratory Science Co., Ltd, Nanjing, 210002, China
| | - Ping Li
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
| | - Dongsheng Chen
- The State Key Laboratory of Neurology and Oncology Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing Simcere Medical Laboratory Science Co., Ltd, Nanjing, 210002, China.
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 121001, China.
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Kong S, Pan H, Zhang YW, Wang F, Chen J, Dong J, Yin C, Wu J, Zhou D, Peng J, Ma J, Zhou J, Ge D, Lu Y, Wei DD, Fang J, Han W, Shen C, Koeffler HP, Wang B, Jiang Y, Jiang YY. Targeting aldehyde dehydrogenase ALDH3A1 increases ferroptosis vulnerability in squamous cancer. Oncogene 2025; 44:1037-1050. [PMID: 39863749 DOI: 10.1038/s41388-025-03277-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 12/15/2024] [Accepted: 01/14/2025] [Indexed: 01/27/2025]
Abstract
Ferroptosis is a unique modality of regulated cell death induced by excessive lipid peroxidation, playing a crucial role in tumor suppression and providing potential therapeutic strategy for cancer treatment. Here, we find that aldehyde dehydrogenase-ALDH3A1 tightly links to ferroptosis in squamous cell carcinomas (SCCs). Functional assays demonstrate the enzymatic activity-dependent regulation of ALDH3A1 in protecting SCC cells against ferroptosis through catalyzing aldehydes and mitigating lipid peroxidation. Furthermore, a specific covalent inhibitor of ALDH3A1-EN40 significantly enhances the ferroptosis sensitivity induced by the ferroptosis inducer. The combination of EN40 and a ferroptosis inducer exhibits a synergistic effect, effectively inhibiting the proliferation of SCC cells/organoids and suppressing tumor growth both in vitro and in vivo. On mechanism, high expression of ALDH3A1 is transcriptionally governed by TP63, which binds to super-enhancer of ALDH3A1. Collectively, our findings reveal a yet-unrecognized function of ALDH3A1 exploited by SCC cells to evade ferroptosis, and targeting ALDH3A1 may enhance the effect of ferroptosis-induced therapy in SCCs.
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Affiliation(s)
- Shuai Kong
- Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- University of Science and Technology of China, Hefei, 230026, China
| | - Huaguang Pan
- Department of Thoracic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Yuan-Wei Zhang
- Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
| | - Fei Wang
- Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- University of Science and Technology of China, Hefei, 230026, China
| | - Jian Chen
- Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
| | - Jinxiu Dong
- Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
| | - Chuntong Yin
- Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- Department of Thoracic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Jiaqi Wu
- Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
| | - Dan Zhou
- Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
| | - Jingyi Peng
- Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- University of Science and Technology of China, Hefei, 230026, China
| | - Junboya Ma
- Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- University of Science and Technology of China, Hefei, 230026, China
| | - Jianian Zhou
- Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- University of Science and Technology of China, Hefei, 230026, China
| | - Dianlong Ge
- Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
| | - Yan Lu
- Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
| | - Dan-Dan Wei
- Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- University of Science and Technology of China, Hefei, 230026, China
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China
| | - Jinman Fang
- Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
- University of Science and Technology of China, Hefei, 230026, China
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China
| | - Wei Han
- Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
| | - Chengyin Shen
- Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China
| | - H Phillip Koeffler
- Department of Medicine, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Boshi Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China.
| | - Yuan Jiang
- Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.
- University of Science and Technology of China, Hefei, 230026, China.
| | - Yan-Yi Jiang
- Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.
- University of Science and Technology of China, Hefei, 230026, China.
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43
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Krause MJ, Sinkala M, Ramesar R. Distinct dysregulated pathways in sporadic and Lynch syndrome-associated colorectal cancer offer insights for targeted treatment. FEBS Lett 2025; 599:1006-1028. [PMID: 39973357 PMCID: PMC11995676 DOI: 10.1002/1873-3468.70010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 01/22/2025] [Accepted: 01/28/2025] [Indexed: 02/21/2025]
Abstract
Lynch syndrome (LS) is a hereditary disorder that increases the risk of colorectal cancer (CRC) due to constitutional pathogenic variants in mismatch repair (MMR) genes. When coupled with somatic mutations in the same gene, MMR deficiency occurs. However, the mechanisms driving cancer development remain unclear. This study aimed to identify distinct molecular drivers in LS-associated and sporadic CRC. We found that PI3K-Akt signalling is dysregulated in LS-associated CRC, while Wnt signalling predominates in sporadic CRC. Moreover, our findings highlight the therapeutic potential of PI3K-Akt pathway inhibitors, such as taselisib, for LS-associated CRC patients with high pathway dependency. Similarly, Wnt signalling pathway inhibitors, such as XAV939, offer a promising therapeutic approach for sporadic CRC. These findings underscore the importance of understanding the biological basis of disease for developing targeted therapies tailored to CRC subtype-specific oncogenic pathways.
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Affiliation(s)
- May J. Krause
- UCT MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Diseases and Molecular MedicineFaculty of Health Sciences, University of Cape TownSouth Africa
| | - Musalula Sinkala
- Computational Biology Division, Department of Integrative Biomedical Sciences, School of Health SciencesUniversity of Cape TownSouth Africa
| | - Raj Ramesar
- UCT MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Diseases and Molecular MedicineFaculty of Health Sciences, University of Cape TownSouth Africa
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44
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Varney SD, Erkes DA, Mersky GL, Mustafa MU, Chua V, Chervoneva I, Purwin TJ, Alnemri E, Aplin AE. Metabolic Inhibition Induces Pyroptosis in Uveal Melanoma. Mol Cancer Res 2025; 23:350-362. [PMID: 39670827 PMCID: PMC11961327 DOI: 10.1158/1541-7786.mcr-24-0508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 11/02/2024] [Accepted: 12/11/2024] [Indexed: 12/14/2024]
Abstract
Few treatment options are available for patients with metastatic uveal melanoma. Although the bispecific tebentafusp is FDA approved, immunotherapy has largely failed, likely given the poorly immunogenic nature of uveal melanoma. Treatment options that improve the recognition of uveal melanoma by the immune system may be key to reducing disease burden. We investigated whether uveal melanoma has the ability to undergo pyroptosis, a form of immunogenic cell death. Publicly available patient data and cell line analysis showed that uveal melanoma expressed the machinery needed for pyroptosis, including gasdermins D and E (GSDMD and E), caspases 1, 3, 4, and 8, and ninjurin-1. We induced cleavage of GSDMs in uveal melanoma cell lines treated with metabolic inhibitors. In particular, the carnitine palmitoyltransferase 1 (CPT1) inhibitor, etomoxir, induced propidium iodide uptake, caspase 3 cleavage, and the release of HMGB1 and IL-1β, indicating that the observed cleavage of GSDMs led to pyroptosis. Importantly, a gene signature reflecting CPT1A activity correlated with poor prognosis in patients with uveal melanoma and knockdown of CPT1A also induced pyroptosis. Etomoxir-induced pyroptosis was dependent on GSDME but not on GSDMD, and a pyroptosis gene signature correlated with immune infiltration and improved response to immune checkpoint blockade in a set of patients with uveal melanoma. Together, these data show that metabolic inhibitors can induce pyroptosis in uveal melanoma cell lines, potentially offering an approach to enhance inflammation-mediated immune targeting in patients with metastatic uveal melanoma. Implications: Induction of pyroptosis by metabolic inhibition may alter the tumor immune microenvironment and improve the efficacy of immunotherapy in uveal melanoma.
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Affiliation(s)
- Scott D. Varney
- Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107 USA
| | - Dan A. Erkes
- Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107 USA
| | - Glenn L. Mersky
- Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107 USA
| | - Manal U. Mustafa
- Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107 USA
| | - Vivian Chua
- Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107 USA
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, Perth, WA 6027, Australia
- Centre for Precision Health, Edith Cowan University, Joondalup, Perth, WA 6027, Australia
| | - Inna Chervoneva
- Division of Biostatistics, Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Timothy J. Purwin
- Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107 USA
| | - Emad Alnemri
- Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107 USA
- Sidney Kimmel Comprehensive Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107 USA
| | - Andrew E. Aplin
- Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107 USA
- Sidney Kimmel Comprehensive Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107 USA
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45
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Pinto R, Vedeld HM, Lind GE, Jeanmougin M. Unraveling epigenetic heterogeneity across gastrointestinal adenocarcinomas through a standardized analytical framework. Mol Oncol 2025; 19:1117-1131. [PMID: 39696831 PMCID: PMC11977639 DOI: 10.1002/1878-0261.13772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 09/30/2024] [Accepted: 10/31/2024] [Indexed: 12/20/2024] Open
Abstract
In this study, we propose an alternative approach for stratifying genome-scale DNA methylation profiles of gastrointestinal (GI) adenocarcinomas based on a robust analytical framework. A set of 978 GI adenocarcinomas and 120 adjacent normal tissues from public repositories was quality controlled and analyzed. Hierarchical consensus clustering of the tumors, based on differential epigenetic variability between malignant and normal samples, identified six distinct subtypes defined either by a pan-GI or a lower GI-specific phenotype. In addition to methylation levels, aberrant methylation frequencies and the degree of DNA methylation instability contributed to the characterization of each subtype. We found significant differences in the outcome of patients, with the poorest overall survival seen for those belonging to a pan-GI subtype with infrequent aberrant methylation. In conclusion, our standardized approach contributes to a refined characterization of the epigenetic heterogeneity in GI adenocarcinomas, offering insights into subtype-specific methylation with the potential to support prognostication.
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Affiliation(s)
- Rita Pinto
- Department of Molecular Oncology, Institute for Cancer ResearchOslo University Hospital – Norwegian Radium HospitalOsloNorway
| | - Hege Marie Vedeld
- Department of Molecular Oncology, Institute for Cancer ResearchOslo University Hospital – Norwegian Radium HospitalOsloNorway
| | - Guro Elisabeth Lind
- Department of Molecular Oncology, Institute for Cancer ResearchOslo University Hospital – Norwegian Radium HospitalOsloNorway
- Department of Biosciences, The Faculty of Mathematics and Natural SciencesUniversity of OsloNorway
| | - Marine Jeanmougin
- Department of Molecular Oncology, Institute for Cancer ResearchOslo University Hospital – Norwegian Radium HospitalOsloNorway
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46
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Liu Y, Dantas E, Ferrer M, Miao T, Qadiri M, Liu Y, Comjean A, Davidson EE, Perrier T, Ahmed T, Hu Y, Goncalves MD, Janowitz T, Perrimon N. Hepatic gluconeogenesis and PDK3 upregulation drive cancer cachexia in flies and mice. Nat Metab 2025; 7:823-841. [PMID: 40275022 PMCID: PMC12021660 DOI: 10.1038/s42255-025-01265-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 03/06/2025] [Indexed: 04/26/2025]
Abstract
Cachexia, a severe wasting syndrome characterized by tumour-induced metabolic dysregulation, is a leading cause of death in people with cancer, yet its underlying mechanisms remain poorly understood. Here we show that a longitudinal full-body single-nuclei-resolution transcriptome analysis in a Drosophila model of cancer cachexia captures interorgan dysregulations. Our study reveals that the tumour-secreted interleukin-like cytokine Upd3 induces fat-body expression of Pepck1 and Pdk, key regulators of gluconeogenesis, disrupting glucose metabolism and contributing to cachexia. Similarly, in mouse cancer cachexia models, we observe IL-6-JAK-STAT-signalling-mediated induction of Pck1 and Pdk3 expression in the liver. Increased expression of these genes in fly, mouse, and human correlates with poor prognosis, and hepatic expression of Pdk3 emerges as a previously unknown mechanism contributing to metabolic dysfunction in cancer cachexia. This study highlights the conserved nature of tumour-induced metabolic disruptions and identifies potential therapeutic targets to mitigate cachexia in people with cancer.
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Affiliation(s)
- Ying Liu
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
| | - Ezequiel Dantas
- Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Miriam Ferrer
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA
| | - Ting Miao
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Mujeeb Qadiri
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Yifang Liu
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Aram Comjean
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Emma E Davidson
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA
- Ohio State University College of Medicine, Columbus, OH, USA
| | - Tiffany Perrier
- Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Tanvir Ahmed
- Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Yanhui Hu
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Marcus D Goncalves
- Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Tobias Janowitz
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA
- Northwell Health Cancer Institute, Northwell Health, New Hyde Park, New York, NY, USA
| | - Norbert Perrimon
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
- Howard Hughes Medical Institute, Boston, MA, USA.
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47
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Liu P, Page D, Ahlquist P, Ong IM, Gitter A. MPAC: a computational framework for inferring pathway activities from multi-omic data. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.06.15.599113. [PMID: 38948762 PMCID: PMC11212914 DOI: 10.1101/2024.06.15.599113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Fully capturing cellular state requires examining genomic, epigenomic, transcriptomic, proteomic, and other assays for a biological sample and comprehensive computational modeling to reason with the complex and sometimes conflicting measurements. Modeling these so-called multi-omic data is especially beneficial in disease analysis, where observations across omic data types may reveal unexpected patient groupings and inform clinical outcomes and treatments. We present Multi-omic Pathway Analysis of Cells (MPAC), a computational framework that interprets multi-omic data through prior knowledge from biological pathways. MPAC uses network relationships encoded in pathways using a factor graph to infer consensus activity levels for proteins and associated pathway entities from multi-omic data, runs permutation testing to eliminate spurious activity predictions, and groups biological samples by pathway activities to prioritize proteins with potential clinical relevance. Using DNA copy number alteration and RNA-seq data from head and neck squamous cell carcinoma patients from The Cancer Genome Atlas as an example, we demonstrate that MPAC predicts a patient subgroup related to immune responses not identified by analysis with either input omic data type alone. Key proteins identified via this subgroup have pathway activities related to clinical outcome as well as immune cell compositions. Our MPAC R package, available at https://bioconductor.org/packages/MPAC, enables similar multi-omic analyses on new datasets.
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Affiliation(s)
- Peng Liu
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - David Page
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Department of Computer Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Paul Ahlquist
- John and Jeanne Rowe Center for Research in Virology, Morgridge Institute for Research, Madison, Wisconsin, United States of America
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Institute for Molecular Virology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Irene M Ong
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Center for Human Genomics and Precision Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Anthony Gitter
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Department of Computer Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- John and Jeanne Rowe Center for Research in Virology, Morgridge Institute for Research, Madison, Wisconsin, United States of America
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48
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Ohshima H, Kobayashi E, Inaba M, Nakazawa R, Hirai N, Ueno T, Nakanishi Y, Endo K, Kondo S, Moriyama-Kita M, Sugimoto H, Yoshizaki T. HRAS Mutations in Head and Neck Carcinomas in Japanese Patients: Clinical Significance, Prognosis, and Therapeutic Potential. Int J Mol Sci 2025; 26:3093. [PMID: 40243851 PMCID: PMC11988887 DOI: 10.3390/ijms26073093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Revised: 03/22/2025] [Accepted: 03/25/2025] [Indexed: 04/18/2025] Open
Abstract
It is well known that a number of head and neck carcinomas are associated with HRAS mutations, and that several cancers with RAS mutations, such as lung cancer, have a poor prognosis. In this study, we evaluated the frequency of HRAS mutations in head and neck carcinomas and characterized the clinical and cell biological features of carcinomas with HRAS mutations. HRAS mutations at codons 12, 13, and 61, mutational hot spots, were evaluated in tissue specimens obtained from 119 Japanese patients treated at our institution. DNA was successfully extracted from 100 specimens, and sequencing was completed. An HRAS mutation was found in 8 (8.0%) cases: 5 (6.1%) out of 82 HNSCCs and 3 (16.7%) out of 18 salivary gland carcinomas. Mutations were found at codons 12 and 61, while none were found at codon 13, which differs from previous reports. The mutation-positive cases had a relatively poor prognosis, consistent with previous reports, and were more frequently accompanied by distant metastasis. HRAS knockdown with siRNA suppressed the in vitro migration ability of HRAS mutation-positive cells but not that of HRAS mutation-negative cells. In conclusion, a positive HRAS mutation could be an indicator of distant metastasis and poor prognosis, as well as a potential therapeutic target.
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Affiliation(s)
| | - Eiji Kobayashi
- Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8640, Japan; (H.O.); (M.I.); (R.N.); (N.H.); (T.U.); (Y.N.); (K.E.); (S.K.); (M.M.-K.); (H.S.); (T.Y.)
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49
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Walter DM, Cho K, Sivakumar S, Lee ITH, Dohlman AB, Shurberg E, Jiang KX, Gupta AA, Frampton GM, Meyerson M. U2AF1 mutations rescue deleterious exon skipping induced by KRAS mutations. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.21.644128. [PMID: 40196662 PMCID: PMC11974705 DOI: 10.1101/2025.03.21.644128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
The mechanisms by which somatic mutations of splicing factors, such as U2AF1S34F in lung adenocarcinoma, contribute to cancer pathogenesis are not well understood. Here, we used prime editing to modify the endogenous U2AF1 gene in lung adenocarcinoma cells and assessed the resulting impact on alternative splicing. These analyses identified KRAS as a key target modulated by U2AF1S34F. One specific KRAS mutation, G12S, generates a cryptic U2AF1 binding site that leads to skipping of KRAS exon 2 and generation of a non-functional KRAS transcript. Expression of the U2AF1S34F mutant reverts this exon skipping and restores KRAS function. Analysis of cancer genomes reveals that U2AF1S34F mutations are enriched in KRASG12S-mutant lung adenocarcinomas. A comprehensive analysis of splicing factor/oncogene mutation co-occurrence in cancer genomes also revealed significant co-enrichment of KRASQ61R and U2AF1I24T mutations. Experimentally, KRASQ61R mutation leads to KRAS exon 3 skipping, which in turn can be rescued by the expression of U2AF1I24T. Analysis of genomic and clinical patient data suggests that both U2AF1 mutations occur secondary to KRAS mutation and are associated with decreased overall patient survival. Our findings provide evidence that splicing factor mutations can rescue splicing defects caused by oncogenic mutations. More broadly, they demonstrate a dynamic process of cascading selection where mutational events are positively selected in cancer genomes as a consequence of earlier mutations.
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Affiliation(s)
- David M Walter
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA
- Department of Genetics, Harvard Medical School, Boston, MA
| | - Katherine Cho
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA
| | | | - Iris T-H Lee
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA
| | - Anders B Dohlman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA
- Department of Genetics, Harvard Medical School, Boston, MA
| | - Ethan Shurberg
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA
| | - Kevin X Jiang
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA
| | - Akansha A Gupta
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA
| | | | - Matthew Meyerson
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA
- Department of Genetics, Harvard Medical School, Boston, MA
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50
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Zhang Q, Cui K, Kong Y, Yu J, Luo Z, Yang X, Gong L, Xie Y, Lin J, Liu C, Zhang Z, Liu Y, Liu B, Liang D, Zeng W, He Z, Lan P. Targeting both the enzymatic and non-enzymatic functions of DHODH as a therapeutic vulnerability in c-Myc-driven cancer. Cell Rep 2025; 44:115327. [PMID: 39977268 DOI: 10.1016/j.celrep.2025.115327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 12/08/2024] [Accepted: 01/28/2025] [Indexed: 02/22/2025] Open
Abstract
c-Myc (Myc)-driven cancers exhibit aggressive phenotypes and therapeutic resistance. Here, integrating CRISPR-Cas9 screening, we identify dihydroorotate dehydrogenase (DHODH) as a promising target in Myc-driven cancer. Mechanistically, DHODH interacts with Myc to stabilize it independently of its enzymatic activity, thereby antagonizing SKP2-mediated polyubiquitination and proteasomal degradation. EN4, a Myc transcriptional activity inhibitor, disrupts DHODH-Myc interaction, promoting Myc degradation via SKP2. Additionally, Myc transcriptionally activates DHODH, enhancing pyrimidine biosynthesis and ferroptosis defense, processes dependent on DHODH enzymatic activity. Clinically, DHODH positively correlates with Myc, activating pyrimidine metabolism and ferroptosis defense in Myc-driven cancers. Hyperactivation of the DHODH-Myc axis is linked to colorectal cancer progression and poor prognosis. Therapeutically, combining EN4 with a DHODH enzymatic inhibitor demonstrates potent antitumor efficacy in Myc-driven colorectal cancer. Overall, our findings elucidate the metabolic and non-metabolic roles of DHODH in Myc-driven cancer, underscoring its dual potential as a therapeutic target addressing both enzymatic and non-enzymatic functions.
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Affiliation(s)
- Qiang Zhang
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong 518107, China.
| | - Kaisa Cui
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China
| | - Yue Kong
- Department of Dermatology, Second Hospital Affiliated to Guangzhou Medical University, Guangzhou, Guangdong 510260, China
| | - Jing Yu
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Zhanhao Luo
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Xiaoya Yang
- School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong 518107, China
| | - Liang Gong
- Shenzhen Key Laboratory of Genome Manipulation and Biosynthesis, Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China
| | - Yanchun Xie
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Jiuxiu Lin
- Department of Dermatology, Second Hospital Affiliated to Guangzhou Medical University, Guangzhou, Guangdong 510260, China
| | - Chen Liu
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Zongjin Zhang
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Yugeng Liu
- Center for Synthetic Microbiome, Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China
| | - Bingxin Liu
- The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Dayi Liang
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Wanyi Zeng
- School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong 518107, China
| | - Zhen He
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China.
| | - Ping Lan
- Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China; State Key Laboratory of Oncology in South China, Guangzhou, Guangdong 510655, China.
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