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Benhassoun R, Morel AP, Jacquot V, Puisieux A, Ouzounova M. The epipliancy journey: Tumor initiation at the mercy of identity crisis and epigenetic drift. Biochim Biophys Acta Rev Cancer 2025; 1880:189307. [PMID: 40174706 DOI: 10.1016/j.bbcan.2025.189307] [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: 10/25/2024] [Revised: 03/05/2025] [Accepted: 03/27/2025] [Indexed: 04/04/2025]
Abstract
Cellular pliancy refers to the unique disposition of different stages of cellular differentiation to transform when exposed to specific oncogenic insults. This concept highlights a strong interconnection between cellular identity and tumorigenesis, and implies overcoming of epigenetic barriers defining cellular states. Emerging evidence suggests that the cell-type-specific response to intrinsic and extrinsic stresses is modulated by accessibility to certain areas of the genome. Understanding the interplay between epigenetic mechanisms, cellular differentiation, and oncogenic insults is crucial for deciphering the complex nature of tumorigenesis and developing targeted therapies. Hence, cellular pliancy relies on a dynamic cooperation between the cellular identity and the cellular context through epigenetic control, including the reactivation of cellular mechanisms, such as epithelial-to-mesenchymal transition (EMT). Such mechanisms and pathways confer plasticity to the cell allowing it to adapt to a hostile environment in a context of tumor initiation, thus changing its cellular identity. Indeed, growing evidence suggests that cancer is a disease of cell identity crisis, whereby differentiated cells lose their defined identity and gain progenitor characteristics. The loss of cell fate commitment is a central feature of tumorigenesis and appears to be a prerequisite for neoplastic transformation. In this context, EMT-inducing transcription factors (EMT-TFs) cooperate with mitogenic oncoproteins to foster malignant transformation. The aberrant activation of EMT-TFs plays an active role in tumor initiation by alleviating key oncosuppressive mechanisms and by endowing cancer cells with stem cell-like properties, including the ability to self-renew, thus changing the course of tumorigenesis. This highly dynamic phenotypic change occurs concomitantly to major epigenome reorganization, a key component of cell differentiation and cancer cell plasticity regulation. The concept of pliancy was initially proposed to address a fundamental question in cancer biology: why are some cells more likely to become cancerous in response to specific oncogenic events at particular developmental stages? We propose the concept of epipliancy, whereby a difference in epigenetic configuration leads to malignant transformation following an oncogenic insult. Here, we present recent studies furthering our understanding of how the epigenetic landscape may impact the modulation of cellular pliancy during early stages of cancer initiation.
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Affiliation(s)
- Rahma Benhassoun
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, France; LabEx DEVweCAN, Université de Lyon, France
| | - Anne-Pierre Morel
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, France; LabEx DEVweCAN, Université de Lyon, France
| | - Victoria Jacquot
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, France
| | - Alain Puisieux
- Equipe labellisée Ligue contre le cancer, U1339 Inserm - UMR3666 CNRS, Paris, France; Institut Curie, PSL Research University, Paris, France
| | - Maria Ouzounova
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, France; LabEx DEVweCAN, Université de Lyon, France.
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Lin HY, Jeon AJ, Chen K, Lee CJM, Wu L, Chong SL, Anene-Nzelu CG, Foo RSY, Chow PKH. The epigenetic basis of hepatocellular carcinoma - mechanisms and potential directions for biomarkers and therapeutics. Br J Cancer 2025; 132:869-887. [PMID: 40057667 DOI: 10.1038/s41416-025-02969-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 01/23/2025] [Accepted: 02/20/2025] [Indexed: 05/17/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth leading cancer worldwide and has complex pathogenesis due to its heterogeneity, along with poor prognoses. Diagnosis is often late as current screening methods have limited sensitivity for early HCC. Moreover, current treatment regimens for intermediate-to-advanced HCC have high resistance rates, no robust predictive biomarkers, and limited survival benefits. A deeper understanding of the molecular biology of HCC may enhance tumor characterization and targeting of key carcinogenic signatures. The epigenetic landscape of HCC includes complex hallmarks of 1) global DNA hypomethylation of oncogenes and hypermethylation of tumor suppressors; 2) histone modifications, altering chromatin accessibility to upregulate oncogene expression, and/or suppress tumor suppressor gene expression; 3) genome-wide rearrangement of chromatin loops facilitating distal enhancer-promoter oncogenic interactions; and 4) RNA regulation via translational repression by microRNAs (miRNAs) and RNA modifications. Additionally, it is useful to consider etiology-specific epigenetic aberrancies, especially in viral hepatitis and metabolic dysfunction-associated steatotic liver disease (MASLD), which are the main risk factors of HCC. This article comprehensively explores the epigenetic signatures in HCC, highlighting their potential as biomarkers and therapeutic targets. Additionally, we examine how etiology-specific epigenetic patterns and the integration of epigenetic therapies with immunotherapy could advance personalized HCC treatment strategies.
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Affiliation(s)
- Hong-Yi Lin
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Ah-Jung Jeon
- Department of Research and Development, Mirxes, Singapore, Singapore
| | - Kaina Chen
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore
| | - Chang Jie Mick Lee
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cardiovascular Research Institute, National University Heart Centre, Singapore, Singapore
| | - Lingyan Wu
- Program in Translational and Clinical Research in Liver Cancer, National Cancer Centre Singapore, Singapore, Singapore
| | - Shay-Lee Chong
- Program in Translational and Clinical Research in Liver Cancer, National Cancer Centre Singapore, Singapore, Singapore
| | | | - Roger Sik-Yin Foo
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cardiovascular Research Institute, National University Heart Centre, Singapore, Singapore
- Department of Cardiology, National University Heart Centre, Singapore, Singapore
| | - Pierce Kah-Hoe Chow
- Program in Translational and Clinical Research in Liver Cancer, National Cancer Centre Singapore, Singapore, Singapore.
- Department of Hepato-pancreato-biliary and Transplant Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital and National Cancer Centre Singapore, Singapore, Singapore.
- Surgery Academic Clinical Programme, Duke-NUS Medical School, Singapore, Singapore.
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Anton L, Cristancho AG, Ferguson B, Ravel J, Elovitz MA. Cervicovaginal microbiome alters transcriptomic and epigenomic signatures across cervicovaginal epithelial barriers. RESEARCH SQUARE 2025:rs.3.rs-6171614. [PMID: 40386438 PMCID: PMC12083688 DOI: 10.21203/rs.3.rs-6171614/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/25/2025]
Abstract
Background The cervicovaginal microbiome plays a critical role in women's health, with microbial communities dominated by Lactobacillus species considered optimal. In contrast, the depletion of lactobacilli and the presence of a diverse array of strict and facultative anaerobes, such as Gardnerella vaginalis, have been linked with adverse reproductive outcomes. Despite these associations, the molecular mechanisms by which host-microbial interactions modulate cervical and vaginal epithelial function remains poorly understood. Results In this study, we used RNA sequencing to characterize the transcriptional response of cervicovaginal epithelial cells exposed to the culture supernatants of common vaginal bacteria. Our findings revealed that G. vaginalis culture supernatants upregulate genes associated with an activated innate immune response and increased cell death. Conversely, Lactobacillus crispatus culture supernatants induced transcriptional changes indicative of epigenomic modeling in ectocervical epithelial cells. Epigenomic modification by L. crispatus, was confirmed by ATAC-sequencing, which demonstrated reduced chromatin accessibility. Conclusions These results provide new insights into host-microbe interactions within the lower reproductive tract and suggests that modulating the vaginal microbiome could offer innovative therapeutic strategies to improve reproductive health.
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Handschin C, Shalhoub H, Mazet A, Guyon C, Dusserre N, Boutet-Robinet E, Oliveira H, Guillermet-Guibert J. Biotechnological advances in 3D modeling of cancer initiation. Examples from pancreatic cancer research and beyond. Biofabrication 2025; 17:022008. [PMID: 40018875 DOI: 10.1088/1758-5090/adb51c] [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: 07/19/2024] [Accepted: 02/12/2025] [Indexed: 03/01/2025]
Abstract
In recent years, biofabrication technologies have garnered significant attention within the scientific community for their potential to create advancedin vitrocancer models. While these technologies have been predominantly applied to model advanced stages of cancer, there exists a pressing need to develop pertinent, reproducible, and sensitive 3D models that mimic cancer initiation lesions within their native tissue microenvironment. Such models hold profound relevance for comprehending the intricacies of cancer initiation, to devise novel strategies for early intervention, and/or to conduct sophisticated toxicology assessments of putative carcinogens. Here, we will explain the pivotal factors that must be faithfully recapitulated when constructing these models, with a specific focus on early pancreatic cancer lesions. By synthesizing the current state of research in this field, we will provide insights into recent advances and breakthroughs. Additionally, we will delineate the key technological and biological challenges that necessitate resolution in future endeavors, thereby paving the way for more accurate and insightfulin vitrocancer initiation models.
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Affiliation(s)
- C Handschin
- Université de Bordeaux, Tissue Bioengineering - BioTis, INSERM U1026, Bordeaux, F-33000, France
- INSERM U1026, ART BioPrint, F-33000 Bordeaux, France
| | - H Shalhoub
- CRCT, Université de Toulouse, Inserm, CNRS, Centre de Recherches en Cancérologie de Toulouse, 2 av Hubert Curien, Toulouse, France
- Labex Toucan, 2 av Hubert Curien, Toulouse, France
| | - A Mazet
- Université de Bordeaux, Tissue Bioengineering - BioTis, INSERM U1026, Bordeaux, F-33000, France
- INSERM U1026, ART BioPrint, F-33000 Bordeaux, France
| | - C Guyon
- CRCT, Université de Toulouse, Inserm, CNRS, Centre de Recherches en Cancérologie de Toulouse, 2 av Hubert Curien, Toulouse, France
- Labex Toucan, 2 av Hubert Curien, Toulouse, France
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UT3, Toulouse, France
| | - N Dusserre
- Université de Bordeaux, Tissue Bioengineering - BioTis, INSERM U1026, Bordeaux, F-33000, France
- INSERM U1026, ART BioPrint, F-33000 Bordeaux, France
| | - E Boutet-Robinet
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UT3, Toulouse, France
| | - H Oliveira
- Université de Bordeaux, Tissue Bioengineering - BioTis, INSERM U1026, Bordeaux, F-33000, France
- INSERM U1026, ART BioPrint, F-33000 Bordeaux, France
| | - J Guillermet-Guibert
- CRCT, Université de Toulouse, Inserm, CNRS, Centre de Recherches en Cancérologie de Toulouse, 2 av Hubert Curien, Toulouse, France
- Labex Toucan, 2 av Hubert Curien, Toulouse, France
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UT3, Toulouse, France
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Saintilnord WN, Hegazy YA, Chesnutt K, Eckstein M, Cassidy RN, Dhahri H, Bennett RL, Melters DP, Lopes E, Fu Z, Lau K, Chandler DP, Poirier MG, Dalal Y, Licht JD, Fondufe-Mittendorf Y. Aberrant expression of histone H2B variants reshape chromatin and alter oncogenic gene expression programs. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.18.624207. [PMID: 39605447 PMCID: PMC11601509 DOI: 10.1101/2024.11.18.624207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Chromatin architecture governs DNA accessibility and gene expression. Thus, any perturbations to chromatin can significantly alter gene expression programs and promote disease. Prior studies demonstrate that every amino acid in a histone is functionally significant, and that even a single amino acid substitution can drive specific cancers. We previously observed that naturally occurring H2B variants are dysregulated during the epithelial to mesenchymal transition (EMT) in bronchial epithelial cells. Naturally occurring H2B variants differ from canonical H2B by only a few amino acids, yet single amino acid changes in other histone variants (e.g., H3.3) can drive cancer. We therefore hypothesized that H2B variants might function like oncohistones, and investigated how they modify chromatin architecture, dynamics, and function. We find that H2B variants are frequently dysregulated in many cancers, and correlate with patient prognosis. Despite high sequence similarity, mutations in each H2B variant tend to occur at specific "hotspots" in cancer. Some H2B variants cause tighter DNA wrapping around nucleosomes, leading to more compact chromatin structures and reduced transcription factor accessibility to nucleosomal DNA. They also altered genome-wide accessibility to oncogenic regulatory elements and genes, with concomitant changes in oncogenic gene expression programs. Although we did not observe changes in cell proliferation or migration in vitro , our Gene Ontology (GO) analyses of ATAC-seq peaks and RNA-seq data indicated significant changes in oncogenic pathways. These findings suggest that H2B variants may influence early-stage, cancer-associated regulatory mechanisms, potentially setting the stage for oncogenesis later on. Thus, H2B variant expression could serve as an early cancer biomarker, and H2B variants might be novel therapeutic targets.
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Fan H, Liang X, Tang Y. Neuroscience in peripheral cancers: tumors hijacking nerves and neuroimmune crosstalk. MedComm (Beijing) 2024; 5:e784. [PMID: 39492832 PMCID: PMC11527832 DOI: 10.1002/mco2.784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/25/2024] [Accepted: 09/25/2024] [Indexed: 11/05/2024] Open
Abstract
Cancer neuroscience is an emerging field that investigates the intricate relationship between the nervous system and cancer, gaining increasing recognition for its importance. The central nervous system governs the development of the nervous system and directly affects brain tumors, and the peripheral nervous system (PNS) shapes the tumor microenvironment (TME) of peripheral tumors. Both systems are crucial in cancer initiation and progression, with recent studies revealing a more intricate role of the PNS within the TME. Tumors not only invade nerves but also persuade them through remodeling to further promote malignancy, creating a bidirectional interaction between nerves and cancers. Notably, immune cells also contribute to this communication, forming a triangular relationship that influences protumor inflammation and the effectiveness of immunotherapy. This review delves into the intricate mechanisms connecting the PNS and tumors, focusing on how various immune cell types influence nerve‒tumor interactions, emphasizing the clinical relevance of nerve‒tumor and nerve‒immune dynamics. By deepening our understanding of the interplay between nerves, cancer, and immune cells, this review has the potential to reshape tumor biology insights, inspire innovative therapies, and improve clinical outcomes for cancer patients.
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Affiliation(s)
- Hua‐Yang Fan
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial SurgeryWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Xin‐Hua Liang
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial SurgeryWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Ya‐Ling Tang
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Oral PathologyWest China Hospital of StomatologySichuan UniversityChengduChina
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7
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Xu M, Hong JJ, Zhang X, Sun M, Liu X, Kang J, Stack H, Fang W, Lei H, Lacoste X, Okada R, Jung R, Nguyen R, Shern JF, Thiele CJ, Liu Z. Targeting SWI/SNF ATPases reduces neuroblastoma cell plasticity. EMBO J 2024; 43:4522-4541. [PMID: 39174852 PMCID: PMC11480351 DOI: 10.1038/s44318-024-00206-1] [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: 09/26/2023] [Revised: 07/01/2024] [Accepted: 07/17/2024] [Indexed: 08/24/2024] Open
Abstract
Tumor cell heterogeneity defines therapy responsiveness in neuroblastoma (NB), a cancer derived from neural crest cells. NB consists of two primary subtypes: adrenergic and mesenchymal. Adrenergic traits predominate in NB tumors, while mesenchymal features becomes enriched post-chemotherapy or after relapse. The interconversion between these subtypes contributes to NB lineage plasticity, but the underlying mechanisms driving this phenotypic switching remain unclear. Here, we demonstrate that SWI/SNF chromatin remodeling complex ATPases are essential in establishing an mesenchymal gene-permissive chromatin state in adrenergic-type NB, facilitating lineage plasticity. Targeting SWI/SNF ATPases with SMARCA2/4 dual degraders effectively inhibits NB cell proliferation, invasion, and notably, cellular plasticity, thereby preventing chemotherapy resistance. Mechanistically, depletion of SWI/SNF ATPases compacts cis-regulatory elements, diminishes enhancer activity, and displaces core transcription factors (MYCN, HAND2, PHOX2B, and GATA3) from DNA, thereby suppressing transcriptional programs associated with plasticity. These findings underscore the pivotal role of SWI/SNF ATPases in driving intrinsic plasticity and therapy resistance in neuroblastoma, highlighting an epigenetic target for combinational treatments in this cancer.
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Affiliation(s)
- Man Xu
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Jason J Hong
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Xiyuan Zhang
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Ming Sun
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Xingyu Liu
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Jeeyoun Kang
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Hannah Stack
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Wendy Fang
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Haiyan Lei
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Xavier Lacoste
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Reona Okada
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Raina Jung
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Rosa Nguyen
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Jack F Shern
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Carol J Thiele
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
| | - Zhihui Liu
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
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Ahmed N, Cavattoni I, Villiers W, Cugno C, Deola S, Mifsud B. Multi-omic analysis of longitudinal acute myeloid leukemia patient samples reveals potential prognostic markers linked to disease progression. Front Genet 2024; 15:1442539. [PMID: 39399221 PMCID: PMC11466779 DOI: 10.3389/fgene.2024.1442539] [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: 06/02/2024] [Accepted: 09/09/2024] [Indexed: 10/15/2024] Open
Abstract
Relapse remains a determinant of treatment failure and contributes significantly to mortality in acute myeloid leukemia (AML) patients. Despite efforts to understand AML progression and relapse mechanisms, findings on acquired gene mutations in relapse vary, suggesting inherent genetic heterogeneity and emphasizing the role of epigenetic modifications. We conducted a multi-omic analysis using Omni-C, ATAC-seq, and RNA-seq on longitudinal samples from two adult AML patients at diagnosis and relapse. Herein, we characterized genetic and epigenetic changes in AML progression to elucidate the underlying mechanisms of relapse. Differential interaction analysis showed significant 3D chromatin landscape reorganization between relapse and diagnosis samples. Comparing global open chromatin profiles revealed that relapse samples had significantly fewer accessible chromatin regions than diagnosis samples. In addition, we discovered that relapse-related upregulation was achieved either by forming new active enhancer contacts or by losing interactions with poised enhancers/potential silencers. Altogether, our study highlights the impact of genetic and epigenetic changes on AML progression, underlining the importance of multi-omic approaches in understanding disease relapse mechanisms and guiding potential therapeutic interventions.
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Affiliation(s)
- Nisar Ahmed
- College of Health and Life Sciences, Genomics and Precision Medicine, Hamad Bin Khalifa University, Doha, Qatar
| | - Irene Cavattoni
- Hematology and Bone Marrow Transplant Unit, Ospedale Centrale Bolzano, Bolzano, Italy
| | - William Villiers
- College of Health and Life Sciences, Genomics and Precision Medicine, Hamad Bin Khalifa University, Doha, Qatar
- Department of Medical and Molecular Genetics, King’s College London, London, United Kingdom
| | - Chiara Cugno
- Advanced Cell Therapy Core, Research, Sidra Medicine, Doha, Qatar
| | - Sara Deola
- Advanced Cell Therapy Core, Research, Sidra Medicine, Doha, Qatar
| | - Borbala Mifsud
- College of Health and Life Sciences, Genomics and Precision Medicine, Hamad Bin Khalifa University, Doha, Qatar
- William Harvey Research Institute, Queen Mary University London, London, United Kingdom
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9
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Yu Q, Zhao J, Yang A, Li X. MLLT6/ATF2 Axis Restrains Breast Cancer Progression by Driving DDIT3/4 Expression. Mol Cancer Res 2024; 22:796-811. [PMID: 38757913 DOI: 10.1158/1541-7786.mcr-23-0648] [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: 08/30/2023] [Revised: 01/11/2024] [Accepted: 05/15/2024] [Indexed: 05/18/2024]
Abstract
Epigenetic deregulation is strongly associated with tumor progression. The identification of natural tumor suppressors to overcome cancer metastasis is urgent for cancer therapy. We investigate whether myeloid/lymphoid or mixed-lineage leukemia translocated (MLLT) family members contribute to breast cancer progression and found that high MLLT6 expression predicted a better prognosis and that gradually decreased MLLT6 expression was accompanied by breast cancer malignancy. MLLT6 was downregulated by hypoxia-induced enrichment of DNMT1 at the MLLT6 promoter. The results of in vitro functional experiments indicated that MLLT6 depletion promoted colony formation and cell migration, probably by hampering apoptosis. RNA profiling revealed that the apoptotic pathway was downregulated following stable knockdown of MLLT6. DNA damage-inducible transcript 3/4 (DDIT3/4) were among the top 10 downregulated genes and may have expression patterns similar to that of MLLT6. Restoring DDIT3/4 expression in cells with MLLT6 depletion blocked colony formation and cell migration and attenuated the successful colonization of breast cancer cells in vivo. We also determined that the transcription factor activating transcription factor 2 is a binding partner of MLLT6 and participates in the MLLT6/ATF2 axis, which was reinforced by inhibition of AKT signaling, in turn inducing DDIT3/4 expression by establishing an active chromatin structure at the DDIT3/4 gene promoters. As MLLT6 promotes breast cancer cell apoptosis by inducing DDIT3/4 expression during metastasis, it could be a novel tumor suppressor. Implications: Control of MLLT6 expression via inhibition of PI3K/AKT kinase activity is a potential therapeutic approach for the management of metastatic breast cancer.
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Affiliation(s)
- Qing Yu
- Department of Clinical Laboratory, Foshan Women and Children Hospital, Foshan, China
| | - Jiayi Zhao
- Department of Clinical Laboratory, Foshan Women and Children Hospital, Foshan, China
| | - Anli Yang
- Department of Breast Oncology, Sun Yat-Sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, China
| | - Xiangxin Li
- Department of Clinical Laboratory, Foshan Women and Children Hospital, Foshan, China
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10
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Al-Ostoot FH, Salah S, Khanum SA. An Overview of Cancer Biology, Pathophysiological Development and It's Treatment Modalities: Current Challenges of Cancer anti-Angiogenic Therapy. Cancer Invest 2024; 42:559-604. [PMID: 38874308 DOI: 10.1080/07357907.2024.2361295] [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: 02/17/2021] [Revised: 11/22/2021] [Accepted: 05/25/2024] [Indexed: 06/15/2024]
Abstract
A number of conditions and factors can cause the transformation of normal cells in the body into malignant tissue by changing the normal functions of a wide range of regulatory, apoptotic, and signal transduction pathways. Despite the current deficiency in fully understanding the mechanism of cancer action accurately and clearly, numerous genes and proteins that are causally involved in the initiation, progression, and metastasis of cancer have been identified. But due to the lack of space and the abundance of details on this complex topic, we have emphasized here more recent advances in our understanding of the principles implied tumor cell transformation, development, invasion, angiogenesis, and metastasis. Inhibition of angiogenesis is a significant strategy for the treatment of various solid tumors, that essentially depend on cutting or at least limiting the supply of blood to micro-regions of tumors, leading to pan-hypoxia and pan-necrosis inside solid tumor tissues. Researchers have continued to enhance the efficiency of anti-angiogenic drugs over the past two decades, to identify their potential in the drug interaction, and to discover reasonable interpretations for possible resistance to treatment. In this review, we have discussed an overview of cancer history and recent methods use in cancer therapy, focusing on anti-angiogenic inhibitors targeting angiogenesis formation. Further, this review has explained the molecular mechanism of action of these anti-angiogenic inhibitors in various tumor types and their limitations use. In addition, we described the synergistic mechanisms of immunotherapy and anti-angiogenic therapy and summarizes current clinical trials of these combinations. Many phase III trials found that combining immunotherapy and anti-angiogenic therapy improved survival. Therefore, targeting the source supply of cancer cells to grow and spread with new anti-angiogenic agents in combination with different conventional therapy is a novel method to reduce cancer progression. The aim of this paper is to overview the varying concepts of cancer focusing on mechanisms involved in tumor angiogenesis and provide an overview of the recent trends in anti-angiogenic strategies for cancer therapy.
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Affiliation(s)
- Fares Hezam Al-Ostoot
- Department of Chemistry, Yuvaraja's College, University of Mysore, Mysuru, India
- Department of Biochemistry, Faculty of Education & Science, Albaydha University, Al-Baydha, Yemen
| | - Salma Salah
- Faculty of Medicine and Health Sciences, Thamar University, Dhamar, Yemen
| | - Shaukath Ara Khanum
- Department of Chemistry, Yuvaraja's College, University of Mysore, Mysuru, India
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11
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Zhang S, Xiao X, Yi Y, Wang X, Zhu L, Shen Y, Lin D, Wu C. Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets. Signal Transduct Target Ther 2024; 9:149. [PMID: 38890350 PMCID: PMC11189549 DOI: 10.1038/s41392-024-01848-7] [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: 01/01/2024] [Revised: 04/23/2024] [Accepted: 04/27/2024] [Indexed: 06/20/2024] Open
Abstract
Tumorigenesis is a multistep process, with oncogenic mutations in a normal cell conferring clonal advantage as the initial event. However, despite pervasive somatic mutations and clonal expansion in normal tissues, their transformation into cancer remains a rare event, indicating the presence of additional driver events for progression to an irreversible, highly heterogeneous, and invasive lesion. Recently, researchers are emphasizing the mechanisms of environmental tumor risk factors and epigenetic alterations that are profoundly influencing early clonal expansion and malignant evolution, independently of inducing mutations. Additionally, clonal evolution in tumorigenesis reflects a multifaceted interplay between cell-intrinsic identities and various cell-extrinsic factors that exert selective pressures to either restrain uncontrolled proliferation or allow specific clones to progress into tumors. However, the mechanisms by which driver events induce both intrinsic cellular competency and remodel environmental stress to facilitate malignant transformation are not fully understood. In this review, we summarize the genetic, epigenetic, and external driver events, and their effects on the co-evolution of the transformed cells and their ecosystem during tumor initiation and early malignant evolution. A deeper understanding of the earliest molecular events holds promise for translational applications, predicting individuals at high-risk of tumor and developing strategies to intercept malignant transformation.
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Affiliation(s)
- Shaosen Zhang
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Xinyi Xiao
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Yonglin Yi
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Xinyu Wang
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Lingxuan Zhu
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Changping Laboratory, 100021, Beijing, China
| | - Yanrong Shen
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Dongxin Lin
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
- Changping Laboratory, 100021, Beijing, China.
- Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China.
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, 510060, China.
| | - Chen Wu
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
- Changping Laboratory, 100021, Beijing, China.
- Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China.
- CAMS Oxford Institute, Chinese Academy of Medical Sciences, 100006, Beijing, China.
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12
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Elovitz M, Anton L, Cristancho A, Ferguson B, Joseph A, Ravel J. Vaginal microbes alter epithelial transcriptome and induce epigenomic modifications providing insight into mechanisms for susceptibility to adverse reproductive outcomes. RESEARCH SQUARE 2024:rs.3.rs-4385224. [PMID: 38854063 PMCID: PMC11160883 DOI: 10.21203/rs.3.rs-4385224/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2024]
Abstract
The cervicovaginal microbiome is highly associated with women's health, with microbial communities dominated by Lactobacillus species considered optimal. Conversely, a lack of lactobacilli and a high abundance of strict and facultative anaerobes, including Gardnerella vaginalis, have been associated with adverse reproductive outcomes. However, how host-microbial interactions alter specific molecular pathways and impact cervical and vaginal epithelial function remains unclear. Using RNA-sequencing, we characterized the in vitro cervicovaginal epithelial transcriptional response to different vaginal bacteria and their culture supernatants. We showed that G. vaginalis upregulates genes associated with an activated innate immune response. Unexpectedly, G. vaginalis specifically induced inflammasome pathways through activation of NLRP3-mediated increases in caspase-1, IL-1β and cell death, while live L. crispatus had minimal transcriptomic changes on epithelial cells. L. crispatus culture supernatants resulted in a shift in the epigenomic landscape of cervical epithelial cells that was confirmed by ATAC-sequencing showing reduced chromatin accessibility. This study reveals new insights into host-microbe interactions in the lower reproductive tract and suggests potential therapeutic strategies leveraging the vaginal microbiome to improve reproductive health.
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13
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Parreno V, Loubiere V, Schuettengruber B, Fritsch L, Rawal CC, Erokhin M, Győrffy B, Normanno D, Di Stefano M, Moreaux J, Butova NL, Chiolo I, Chetverina D, Martinez AM, Cavalli G. Transient loss of Polycomb components induces an epigenetic cancer fate. Nature 2024; 629:688-696. [PMID: 38658752 PMCID: PMC11096130 DOI: 10.1038/s41586-024-07328-w] [Citation(s) in RCA: 58] [Impact Index Per Article: 58.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 03/15/2024] [Indexed: 04/26/2024]
Abstract
Although cancer initiation and progression are generally associated with the accumulation of somatic mutations1,2, substantial epigenomic alterations underlie many aspects of tumorigenesis and cancer susceptibility3-6, suggesting that genetic mechanisms might not be the only drivers of malignant transformation7. However, whether purely non-genetic mechanisms are sufficient to initiate tumorigenesis irrespective of mutations has been unknown. Here, we show that a transient perturbation of transcriptional silencing mediated by Polycomb group proteins is sufficient to induce an irreversible switch to a cancer cell fate in Drosophila. This is linked to the irreversible derepression of genes that can drive tumorigenesis, including members of the JAK-STAT signalling pathway and zfh1, the fly homologue of the ZEB1 oncogene, whose aberrant activation is required for Polycomb perturbation-induced tumorigenesis. These data show that a reversible depletion of Polycomb proteins can induce cancer in the absence of driver mutations, suggesting that tumours can emerge through epigenetic dysregulation leading to inheritance of altered cell fates.
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Affiliation(s)
- V Parreno
- Institute of Human Genetics, CNRS, University of Montpellier, Montpellier, France
| | - V Loubiere
- Institute of Human Genetics, CNRS, University of Montpellier, Montpellier, France
- Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria
| | - B Schuettengruber
- Institute of Human Genetics, CNRS, University of Montpellier, Montpellier, France
| | - L Fritsch
- Institute of Human Genetics, CNRS, University of Montpellier, Montpellier, France
| | - C C Rawal
- University of Southern California, Los Angeles, CA, USA
| | - M Erokhin
- Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia
| | - B Győrffy
- Semmelweis University Department of Bioinformatics, Budapest, Hungary
- Department of Biophysics, Medical School, University of Pécs, Pécs, Hungary
| | - D Normanno
- Institute of Human Genetics, CNRS, University of Montpellier, Montpellier, France
| | - M Di Stefano
- Institute of Human Genetics, CNRS, University of Montpellier, Montpellier, France
| | - J Moreaux
- Institute of Human Genetics, CNRS, University of Montpellier, Montpellier, France
- Department of Biological Hematology, CHU Montpellier, Montpellier, France
- UFR Medicine, University of Montpellier, Montpellier, France
| | - N L Butova
- University of Southern California, Los Angeles, CA, USA
| | - I Chiolo
- University of Southern California, Los Angeles, CA, USA
| | - D Chetverina
- Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia
| | - A-M Martinez
- Institute of Human Genetics, CNRS, University of Montpellier, Montpellier, France.
| | - G Cavalli
- Institute of Human Genetics, CNRS, University of Montpellier, Montpellier, France.
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14
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Kitamura Y, Takahashi K, Maezawa S, Munakata Y, Sakashita A, Kaplan N, Namekawa SH. CTCF-mediated 3D chromatin predetermines the gene expression program in the male germline. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.30.569508. [PMID: 38076840 PMCID: PMC10705413 DOI: 10.1101/2023.11.30.569508] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
Spermatogenesis is a unidirectional differentiation process that generates haploid sperm, but how the gene expression program that directs this process is established is largely unknown. Here we determine the high-resolution 3D chromatin architecture of male germ cells during spermatogenesis and show that CTCF-mediated 3D chromatin predetermines the gene expression program required for spermatogenesis. In undifferentiated spermatogonia, CTCF-mediated chromatin contacts on autosomes pre-establish meiosis-specific super-enhancers (SE). These meiotic SE recruit the master transcription factor A-MYB in meiotic spermatocytes, which strengthens their 3D contacts and instructs a burst of meiotic gene expression. We also find that at the mitosis-to-meiosis transition, the germline-specific Polycomb protein SCML2 resolves chromatin loops that are specific to mitotic spermatogonia. Moreover, SCML2 and A-MYB establish the unique 3D chromatin organization of sex chromosomes during meiotic sex chromosome inactivation. We propose that CTCF-mediated 3D chromatin organization enforces epigenetic priming that directs unidirectional differentiation, thereby determining the cellular identity of the male germline.
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Affiliation(s)
- Yuka Kitamura
- Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, CA, 95616, USA
| | - Kazuki Takahashi
- Division of Reproductive Sciences, Division of Developmental Biology, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - So Maezawa
- Division of Reproductive Sciences, Division of Developmental Biology, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 45229, USA
- Faculty of Science and Technology, Department of Applied Biological Science, Tokyo University of Science, Noda, Chiba, 281-8510, Japan
| | - Yasuhisa Munakata
- Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, CA, 95616, USA
- Division of Reproductive Sciences, Division of Developmental Biology, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Akihiko Sakashita
- Division of Reproductive Sciences, Division of Developmental Biology, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 45229, USA
- Department of Molecular Biology, Keio University School of Medicine, Tokyo, 160-8582 Japan
| | - Noam Kaplan
- Department of Physiology, Biophysics & Systems Biology, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - Satoshi H. Namekawa
- Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, CA, 95616, USA
- Division of Reproductive Sciences, Division of Developmental Biology, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 45229, USA
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15
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Elovitz M, Anton L, Cristancho A, Ferguson B, Joseph A, Ravel J. Vaginal microbes alter epithelial transcriptomic and epigenomic modifications providing insight into the molecular mechanisms for susceptibility to adverse reproductive outcomes. RESEARCH SQUARE 2023:rs.3.rs-3580132. [PMID: 38014044 PMCID: PMC10680926 DOI: 10.21203/rs.3.rs-3580132/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
The cervicovaginal microbiome is highly associated with women's health with microbial communities dominated by Lactobacillus spp. being considered optimal. Conversely, a lack of lactobacilli and a high abundance of strict and facultative anaerobes including Gardnerella vaginalis , have been associated with adverse reproductive outcomes. However, the molecular pathways modulated by microbe interactions with the cervicovaginal epithelia remain unclear. Using RNA-sequencing, we characterize the in vitro cervicovaginal epithelial transcriptional response to different vaginal bacteria and their culture supernatants. We showed that G. vaginalis upregulated genes were associated with an activated innate immune response including anti-microbial peptides and inflammasome pathways, represented by NLRP3-mediated increases in caspase-1, IL-1β and cell death. Cervicovaginal epithelial cells exposed to L. crispatus showed limited transcriptomic changes, while exposure to L. crispatus culture supernatants resulted in a shift in the epigenomic landscape of cervical epithelial cells. ATAC-sequencing confirmed epigenetic changes with reduced chromatin accessibility. This study reveals new insight into host-microbe interactions in the lower reproductive tract and suggest potential therapeutic strategies leveraging the vaginal microbiome to improve reproductive health.
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16
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Lin S, Margueron R, Charafe-Jauffret E, Ginestier C. Disruption of lineage integrity as a precursor to breast tumor initiation. Trends Cell Biol 2023; 33:887-897. [PMID: 37061355 DOI: 10.1016/j.tcb.2023.03.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 03/13/2023] [Accepted: 03/17/2023] [Indexed: 04/17/2023]
Abstract
Increase in lineage infidelity and/or imbalance is frequently observed around the earliest stage of breast tumor initiation. In response to disruption of homeostasis, differentiated cells can partially lose their identity and gain cellular plasticity, a process involving epigenome landscape remodeling. This increase of cellular plasticity may promote the malignant transformation of breast tumors and fuel their heterogeneity. Here, we review recent studies that have yield insights into important regulators of lineage integrity and mechanisms that trigger mammary epithelial lineage derail, and evaluate their impacts on breast tumor development.
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Affiliation(s)
- Shuheng Lin
- CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille Univeristy, Epithelial Stem Cells and Cancer Laboratory, Equipe Labellisée LIGUE Contre le Cancer, Marseille, France
| | - Raphaël Margueron
- Institut Curie, PSL Research University, Sorbonne University, Paris, France
| | - Emmanuelle Charafe-Jauffret
- CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille Univeristy, Epithelial Stem Cells and Cancer Laboratory, Equipe Labellisée LIGUE Contre le Cancer, Marseille, France.
| | - Christophe Ginestier
- CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille Univeristy, Epithelial Stem Cells and Cancer Laboratory, Equipe Labellisée LIGUE Contre le Cancer, Marseille, France.
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17
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Amiri A, Dietz C, Rapp A, Cardoso MC, Stark RW. The cyto-linker and scaffolding protein "plectin" mis-localization leads to softening of cancer cells. NANOSCALE 2023; 15:15008-15026. [PMID: 37668423 DOI: 10.1039/d3nr02226a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/06/2023]
Abstract
Discovering tools to prevent cancer progression requires understanding the fundamental differences between normal and cancer cells. More than a decade ago, atomic force microscopy (AFM) revealed cancer cells' softer body compared to their healthy counterparts. Here, we investigated the mechanism underlying the softening of cancerous cells in comparison with their healthy counterparts based on AFM high resolution stiffness tomography and 3D confocal microscopy. We showed microtubules (MTs) network in invasive ductal carcinoma cell cytoskeleton is basally located and segmented for around 400 nm from the cell periphery. Additionally, the cytoskeleton scaffolding protein plectin exhibits a mis-localization from the cytoplasm to the surface of cells in the carcinoma which justifies the dissociation of the MT network from the cell's cortex. Furthermore, the assessment of MTs' persistence length using a worm-like-chain (WLC) model in high resolution AFM images showed lower persistence length of the single MTs in ductal carcinoma compared to that in the normal state. Overall, these tuned mechanics support the invasive cells to ascertain more flexibility under compressive forces in small deformations. These data provide new insights into the structural origins of cancer aids in progression.
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Affiliation(s)
- Anahid Amiri
- Physics of Surfaces, Institute of Materials Science, Technical University of Darmstadt, Alarich-Weiss-Str. 2, 64287 Darmstadt, Germany.
| | - Christian Dietz
- Physics of Surfaces, Institute of Materials Science, Technical University of Darmstadt, Alarich-Weiss-Str. 2, 64287 Darmstadt, Germany.
| | - Alexander Rapp
- Cell Biology and Epigenetics, Department of Biology, Technical University of Darmstadt, 64287 Darmstadt, Germany
| | - M Cristina Cardoso
- Cell Biology and Epigenetics, Department of Biology, Technical University of Darmstadt, 64287 Darmstadt, Germany
| | - Robert W Stark
- Physics of Surfaces, Institute of Materials Science, Technical University of Darmstadt, Alarich-Weiss-Str. 2, 64287 Darmstadt, Germany.
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18
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Panzeri I, Fagnocchi L, Apostle S, Tompkins M, Wolfrum E, Madaj Z, Hostetter G, Liu Y, Schaefer K, Chih-Hsiang Y, Bergsma A, Drougard A, Dror E, PERMUTE, Chandler D, Schramek D, Triche TJ, Pospisilik JA. Developmental priming of cancer susceptibility. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.12.557446. [PMID: 37745326 PMCID: PMC10515831 DOI: 10.1101/2023.09.12.557446] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
DNA mutations are necessary drivers of cancer, yet only a small subset of mutated cells go on to cause the disease. To date, the mechanisms that determine which rare subset of cells transform and initiate tumorigenesis remain unclear. Here, we take advantage of a unique model of intrinsic developmental heterogeneity (Trim28+/D9) and demonstrate that stochastic early life epigenetic variation can trigger distinct cancer-susceptibility 'states' in adulthood. We show that these developmentally primed states are characterized by differential methylation patterns at typically silenced heterochromatin, and that these epigenetic signatures are detectable as early as 10 days of age. The differentially methylated loci are enriched for genes with known oncogenic potential. These same genes are frequently mutated in human cancers, and their dysregulation correlates with poor prognosis. These results provide proof-of-concept that intrinsic developmental heterogeneity can prime individual, life-long cancer risk.
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Affiliation(s)
- Ilaria Panzeri
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
- Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Luca Fagnocchi
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
| | - Stefanos Apostle
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
| | - Megan Tompkins
- Vivarium and Transgenics Core, Van Andel Institute, Grand Rapids, MI, USA
| | - Emily Wolfrum
- Bioinformatics and Biostatistics Core, Van Andel Institute, Grand Rapids, MI, USA
| | - Zachary Madaj
- Bioinformatics and Biostatistics Core, Van Andel Institute, Grand Rapids, MI, USA
| | - Galen Hostetter
- Pathology and Biorepository Core, Van Andel Institute, Grand Rapids, MI, USA
| | - Yanqing Liu
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
| | - Kristen Schaefer
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
- Department of Genetics and Genome Science, Case Western Reserve University, Cleveland, Ohio, USA
| | - Yang Chih-Hsiang
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
- Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
- Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA USA
| | - Alexis Bergsma
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
- Parkinson’s Disease Center, Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
| | - Anne Drougard
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
| | - Erez Dror
- Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | | | - Darrell Chandler
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
| | - Daniel Schramek
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Timothy J. Triche
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
| | - J. Andrew Pospisilik
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
- Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
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19
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Dan WY, Zhou GZ, Peng LH, Pan F. Update and latest advances in mechanisms and management of colitis-associated colorectal cancer. World J Gastrointest Oncol 2023; 15:1317-1331. [PMID: 37663937 PMCID: PMC10473934 DOI: 10.4251/wjgo.v15.i8.1317] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 07/03/2023] [Accepted: 07/25/2023] [Indexed: 08/10/2023] Open
Abstract
Colitis-associated colorectal cancer (CAC) is defined as a specific cluster of colorectal cancers that develop as a result of prolonged colitis in patients with inflammatory bowel disease (IBD). Patients with IBD, including ulcerative colitis and Crohn's disease, are known to have an increased risk of developing CAC. Although the incidence of CAC has significantly decreased over the past few decades, individuals with CAC have increased mortality compared to individuals with sporadic colorectal cancer, and the incidence of CAC increases with duration. Chronic inflammation is generally recognized as a major contributor to the pathogenesis of CAC. CAC has been shown to progress from colitis to dysplasia and finally to carcinoma. Accumulating evidence suggests that multiple immune-mediated pathways, DNA damage pathways, and pathogens are involved in the pathogenesis of CAC. Over the past decade, there has been an increasing effort to develop clinical approaches that could help improve outcomes for CAC patients. Colonoscopic surveillance plays an important role in reducing the risk of advanced and interval cancers. It is generally recommended that CAC patients undergo endoscopic removal or colectomy. This review summarizes the current understanding of CAC, particularly its epidemiology, mechanisms, and management. It focuses on the mechanisms that contribute to the development of CAC, covering advances in genomics, immunology, and the microbiome; presents evidence for management strategies, including endoscopy and colectomy; and discusses new strategies to interfere with the process and development of CAC. These scientific findings will pave the way for the management of CAC in the near future.
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Affiliation(s)
- Wan-Yue Dan
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
- Medical School, Nankai University, Tianjin 300071, China
| | - Guan-Zhou Zhou
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
- Medical School, Nankai University, Tianjin 300071, China
| | - Li-Hua Peng
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Fei Pan
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
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20
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He X, Zhong X, Fang Y, Hu Z, Chen Z, Wang Y, Huang H, Zhao S, Li D, Wei P. AF9 sustains glycolysis in colorectal cancer via H3K9ac-mediated PCK2 and FBP1 transcription. Clin Transl Med 2023; 13:e1352. [PMID: 37565737 PMCID: PMC10413954 DOI: 10.1002/ctm2.1352] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 07/18/2023] [Accepted: 07/24/2023] [Indexed: 08/12/2023] Open
Abstract
BACKGROUND The tumourigenesis of various cancers is influenced by epigenetic deregulation. Among 591 epigenetic regulator factors (ERFs) examined, AF9 showed significant inhibition of malignancy in colorectal cancer (CRC) based on our wound healing assays. However, the precise role of AF9 in CRC remains to be explored. METHODS To investigate the function of AF9 in CRC, we utilised small interfering RNAs (siRNAs) to knock down the expression of 591 ERFs. Subsequently, we performed wound healing assays to evaluate cell proliferation and migration. In vitro and in vivo assays were conducted to elucidate the potential impact of AF9 in CRC. Clinical samples were analysed to assess the association between AF9 expression and CRC prognosis. Additionally, an Azoxymethane-Dextran Sodium Sulfate (AOM/DSS) induced CRC AF9IEC-/- mouse model was employed to confirm the role of AF9 in CRC. To identify the target gene of AF9, RNA-seq and coimmunoprecipitation analyses were performed. Furthermore, bioinformatics prediction was applied to identify potential miRNAs that target AF9. RESULTS Among the 591 ERFs examined, AF9 exhibited downregulation in CRC and showed a positive correlation with prolonged survival in CRC patients. In vitro and in vivo assays proved that depletion of AF9 could promote cell proliferation, migration as well as glycolysis. Specifically, knockout of MLLT3 (AF9) in intestinal epithelial cells significantly increased tumour formation induced by AOM/DSS. We also identified miR-145 could target 3'untranslated region of AF9 to suppress AF9 expression. Loss of AF9 led to decreased expression of gluconeogenic genes, including phosphoenolpyruvate carboxykinase 2 (PCK2) and fructose 1,6-bisphosphatase 1 (FBP1), subsequently promoting glucose consumption and tumourigenesis. CONCLUSIONS AF9 is essential for the upregulation of PCK2 and FBP1, and the disruption of the miR-145/AF9 axis may serve as a potential target for the development of CRC therapeutics.
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Affiliation(s)
- Xuefeng He
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College Fudan UniversityShanghaiChina
| | - Xinyang Zhong
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College Fudan UniversityShanghaiChina
| | - Yi Fang
- Emergency DepartmentShanghai Tenth People's HospitalShanghaiChina
| | - Zijuan Hu
- Department of PathologyFudan University Shanghai Cancer CenterShanghaiChina
- Cancer InstituteFudan University Shanghai Cancer CenterShanghaiChina
- Institute of PathologyFudan UniversityShanghaiChina
- Department of OncologyShanghai Medical College Fudan UniversityShanghaiChina
| | - Zhiyu Chen
- Department of OncologyShanghai Medical College Fudan UniversityShanghaiChina
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghaiChina
| | - Yaxian Wang
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College Fudan UniversityShanghaiChina
| | - Huixia Huang
- Department of PathologyFudan University Shanghai Cancer CenterShanghaiChina
- Cancer InstituteFudan University Shanghai Cancer CenterShanghaiChina
- Institute of PathologyFudan UniversityShanghaiChina
- Department of OncologyShanghai Medical College Fudan UniversityShanghaiChina
| | - Senlin Zhao
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College Fudan UniversityShanghaiChina
| | - Dawei Li
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College Fudan UniversityShanghaiChina
| | - Ping Wei
- Department of PathologyFudan University Shanghai Cancer CenterShanghaiChina
- Cancer InstituteFudan University Shanghai Cancer CenterShanghaiChina
- Institute of PathologyFudan UniversityShanghaiChina
- Department of OncologyShanghai Medical College Fudan UniversityShanghaiChina
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21
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Rane JK, Frankell AM, Weeden CE, Swanton C. Clonal Evolution in Healthy and Premalignant Tissues: Implications for Early Cancer Interception Strategies. Cancer Prev Res (Phila) 2023; 16:369-378. [PMID: 36930945 PMCID: PMC7614725 DOI: 10.1158/1940-6207.capr-22-0469] [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: 01/13/2023] [Revised: 02/17/2023] [Accepted: 03/14/2023] [Indexed: 03/19/2023]
Abstract
Histologically normal human tissues accumulate significant mutational burden with age. The extent and spectra of mutagenesis are comparable both in rapidly proliferating and post-mitotic tissues and in stem cells compared with their differentiated progeny. Some of these mutations provide increased fitness, giving rise to clones which, at times, can replace the entire surface area of tissues. Compared with cancer, somatic mutations in histologically normal tissues are primarily single-nucleotide variations. Interestingly though, the presence of these mutations and positive clonal selection in isolation remains a poor indicator of potential future cancer transformation in solid tissues. Common clonally expanded mutations in histologically normal tissues also do not always represent the most frequent early mutations in cancers of corresponding tissues, indicating differences in selection pressures. Preliminary evidence implies that stroma and immune system co-evolve with age, which may impact selection dynamics. In this review, we will explore the mutational landscape of histologically normal and premalignant human somatic tissues in detail and discuss cell-intrinsic and environmental factors that can determine the fate of positively selected mutations within them. Precisely pinpointing these determinants of cancer transformation would aid development of early cancer interventional and prevention strategies.
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Affiliation(s)
- Jayant K. Rane
- University College London Cancer Institute, London, UK
- Department of Clinical Oncology, University College London Hospitals, London, UK
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - Alexander M. Frankell
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | - Clare E. Weeden
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - Charles Swanton
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Department of Medical Oncology, University College London Hospitals, London, UK
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22
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Kumar K, Kumar S, Datta K, Fornace AJ, Suman S. High-LET-Radiation-Induced Persistent DNA Damage Response Signaling and Gastrointestinal Cancer Development. Curr Oncol 2023; 30:5497-5514. [PMID: 37366899 DOI: 10.3390/curroncol30060416] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/05/2023] [Accepted: 06/06/2023] [Indexed: 06/28/2023] Open
Abstract
Ionizing radiation (IR) dose, dose rate, and linear energy transfer (LET) determine cellular DNA damage quality and quantity. High-LET heavy ions are prevalent in the deep space environment and can deposit a much greater fraction of total energy in a shorter distance within a cell, causing extensive DNA damage relative to the same dose of low-LET photon radiation. Based on the DNA damage tolerance of a cell, cellular responses are initiated for recovery, cell death, senescence, or proliferation, which are determined through a concerted action of signaling networks classified as DNA damage response (DDR) signaling. The IR-induced DDR initiates cell cycle arrest to repair damaged DNA. When DNA damage is beyond the cellular repair capacity, the DDR for cell death is initiated. An alternative DDR-associated anti-proliferative pathway is the onset of cellular senescence with persistent cell cycle arrest, which is primarily a defense mechanism against oncogenesis. Ongoing DNA damage accumulation below the cell death threshold but above the senescence threshold, along with persistent SASP signaling after chronic exposure to space radiation, pose an increased risk of tumorigenesis in the proliferative gastrointestinal (GI) epithelium, where a subset of IR-induced senescent cells can acquire a senescence-associated secretory phenotype (SASP) and potentially drive oncogenic signaling in nearby bystander cells. Moreover, DDR alterations could result in both somatic gene mutations as well as activation of the pro-inflammatory, pro-oncogenic SASP signaling known to accelerate adenoma-to-carcinoma progression during radiation-induced GI cancer development. In this review, we describe the complex interplay between persistent DNA damage, DDR, cellular senescence, and SASP-associated pro-inflammatory oncogenic signaling in the context of GI carcinogenesis.
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Affiliation(s)
- Kamendra Kumar
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Santosh Kumar
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Kamal Datta
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Department of Biochemistry and Molecular & Cellular Biology and Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Albert J Fornace
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Department of Biochemistry and Molecular & Cellular Biology and Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Shubhankar Suman
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Department of Biochemistry and Molecular & Cellular Biology and Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA
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23
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Verma T, Natu A, Khade B, Gera P, Gupta S. An increase in polyadenylation of histone isoforms, Hist1h2ah and Hist2h3c2, is governed by 3'-UTR in de-differentiated and undifferentiated hepatocyte. Exp Biol Med (Maywood) 2023; 248:948-958. [PMID: 37021545 PMCID: PMC10525402 DOI: 10.1177/15353702231160328] [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: 08/22/2022] [Accepted: 02/09/2023] [Indexed: 04/07/2023] Open
Abstract
Replication-dependent histones have a stem-loop structure at the 3' end of messenger RNA (mRNA) and are stabilized by stem-loop binding protein (SLBP). Moreover, loss of SLBP and imbalance in the level of ARE (adenylate-uridylate-rich elements)-binding proteins, HuR, and BRF1 are associated with the polyadenylation of canonical histone mRNAs under different physiological conditions. Previous studies from the lab have shown increased protein levels of H2A1H and H3.2 in N-nitrosodiethylamine (NDEA)-induced hepatocellular carcinoma (HCC). In this study, we report that increase in the polyadenylation of histone mRNA contributes to increased levels of H2A1H and H3.2 in NDEA-induced HCC. The persistent exposure to carcinogen with polyadenylation of histone mRNA increases the total histone pool resulting in aneuploidy. The embryonic liver has also shown increased polyadenylated histone isoforms, Hist1h2ah and Hist2h3c2, primarily contributing to their increased protein levels. The increase in polyadenylation of histone mRNA in HCC and e15 are in coherence with the decrease in SLBP and BRF1 with an increase in HuR. Our studies in neoplastic CL38 cell line showed that direct stress on the cells induces downregulation of SLBP with enhanced histone isoform polyadenylation. Moreover, the polyadenylation is related to increase in activated MAP kinases, p38, ERK, and JNK in HCC liver tumor tissues and CL38 cells treated with arsenic. Our data suggest that SLBP degrades under stress, destabilizing the stem-loop, elongating histone isoforms mRNA with 3' polyadenylated tail with increase of HuR and decrease of BRF1. Overall, our results indicate that SLBP may play an essential part in cell proliferation, at least in persistent exposure to stress, by mediating the stabilization of histone isoforms throughout the cell cycle.
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Affiliation(s)
- Tripti Verma
- Epigenetics and Chromatin Biology Group, Gupta Lab, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India
- Homi Bhabha National Institute, Mumbai 400094, India
| | - Abhiram Natu
- Epigenetics and Chromatin Biology Group, Gupta Lab, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India
- Homi Bhabha National Institute, Mumbai 400094, India
| | - Bharat Khade
- Epigenetics and Chromatin Biology Group, Gupta Lab, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India
| | - Poonam Gera
- Biorepository, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India
| | - Sanjay Gupta
- Epigenetics and Chromatin Biology Group, Gupta Lab, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India
- Homi Bhabha National Institute, Mumbai 400094, India
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24
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Kurma K, Alix-Panabières C. Mechanobiology and survival strategies of circulating tumor cells: a process towards the invasive and metastatic phenotype. Front Cell Dev Biol 2023; 11:1188499. [PMID: 37215087 PMCID: PMC10196185 DOI: 10.3389/fcell.2023.1188499] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 04/18/2023] [Indexed: 05/24/2023] Open
Abstract
Metastatic progression is the deadliest feature of cancer. Cancer cell growth, invasion, intravasation, circulation, arrest/adhesion and extravasation require specific mechanical properties to allow cell survival and the completion of the metastatic cascade. Circulating tumor cells (CTCs) come into contact with the capillary bed during extravasation/intravasation at the beginning of the metastatic cascade. However, CTC mechanobiology and survival strategies in the bloodstream, and specifically in the microcirculation, are not well known. A fraction of CTCs can extravasate and colonize distant areas despite the biomechanical constriction forces that are exerted by the microcirculation and that strongly decrease tumor cell survival. Furthermore, accumulating evidence shows that several CTC adaptations, via molecular factors and interactions with blood components (e.g., immune cells and platelets inside capillaries), may promote metastasis formation. To better understand CTC journey in the microcirculation as part of the metastatic cascade, we reviewed how CTC mechanobiology and interaction with other cell types in the bloodstream help them to survive the harsh conditions in the circulatory system and to metastasize in distant organs.
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Affiliation(s)
- Keerthi Kurma
- Laboratory of Rare Human Circulating Cells (LCCRH), University Medical Centre of Montpellier, Montpellier, France
- CREEC/CANECEV, MIVEGEC (CREES), University of Montpellier, CNRS, IRD, Montpellier, France
- European Liquid Biopsy Society (E LBS), Hamburg, Germany
| | - Catherine Alix-Panabières
- Laboratory of Rare Human Circulating Cells (LCCRH), University Medical Centre of Montpellier, Montpellier, France
- CREEC/CANECEV, MIVEGEC (CREES), University of Montpellier, CNRS, IRD, Montpellier, France
- European Liquid Biopsy Society (E LBS), Hamburg, Germany
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25
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Qiu Q, Sun Y, Yang L, Li Q, Feng Y, Li M, Yin Y, Zheng L, Li N, Qiu H, Cui X, He W, Wang B, Pan C, Wang Z, Huang J, Sample KM, Li Z, Hu Y. TSPAN32 suppresses chronic myeloid leukemia pathogenesis and progression by stabilizing PTEN. Signal Transduct Target Ther 2023; 8:90. [PMID: 36854750 PMCID: PMC9974991 DOI: 10.1038/s41392-022-01290-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 10/16/2022] [Accepted: 12/02/2022] [Indexed: 03/02/2023] Open
Abstract
We report herein that TSPAN32 is a key node factor for Philadelphia (Ph+) leukemia pathogenesis. We found that TSPAN32 expression was repressed by BCR-ABL and ectopic TSPAN32 expression upon Imatinib treatment inhibited the proliferation of Ph+ cell lines. Tspan32 overexpression significantly prevented BCR-ABL induced leukemia progression in a murine model and impaired leukemia stem cell (LSC) proliferation. LSCs represent an obstacle for chronic myeloid leukemia (CML) elimination, which continually replenish leukemia cells and are associated with disease relapse. Therefore, the identification of essential targets that contribute to the survival and self-renewal of LSCs is important for novel curative CML. Mechanistically, TSPAN32 was shown to interact with PTEN, increased its protein level and caused a reduction in PI3K-AKT signaling activity. We also found that TSPAN32 was repressed by BCR-ABL via the suppression of an important transcription factor, TAL1. Ectopic expression of TAL1 significantly increased TSPAN32 mRNA and protein level, which indicated that BCR-ABL repressed TSPAN32 transcription by decreasing TAL1 expression. Overall, we identified a new signaling axis composed of "BCR-ABL-TAL1-TSPAN32-PTEN-PI3K-AKT". Our findings further complement the known mechanisms underlying the transformation potential of BCR-ABL in CML pathogenesis. This new signaling axis also provides a potential means to target PI3K-AKT for CML treatment.
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Affiliation(s)
- Qiang Qiu
- Department of Thyroid Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China
| | - Yuanyuan Sun
- Department of Thyroid Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China
| | - Linyu Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China
| | - Qingqing Li
- Department of Thyroid Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China
| | - Yunyu Feng
- Department of Thyroid Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China
| | - Mengyuan Li
- Department of Thyroid Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China
| | - Yuexia Yin
- Department of Thyroid Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China
| | - Li Zheng
- Department of Thyroid Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China
| | - Ning Li
- Department of Thyroid Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China
| | - Huandi Qiu
- Department of Thyroid Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China
| | - Xue Cui
- Department of Thyroid Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China
| | - Wei He
- Department of Thyroid Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China
| | - Bochuan Wang
- Department of Thyroid Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China
| | - Cong Pan
- Department of Thyroid Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China
| | - Zi Wang
- Department of Oncology, Guizhou Provincial People's Hospital, Guiyang, Guizhou, China
| | - Juan Huang
- Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
| | - Klarke M Sample
- Institute of Life Science, eBond Pharmaceutical Technology Ltd., Chengdu, China
| | - Zhihui Li
- Laboratory of thyroid and parathyroid disease, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Thyroid Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yiguo Hu
- Department of Thyroid Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China.
- Department of Thyroid Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Xie S, Choudhari S, Wu CL, Abramson K, Corcoran D, Gregory SG, Thimmapuram J, Guilak F, Little D. Aging and obesity prime the methylome and transcriptome of adipose stem cells for disease and dysfunction. FASEB J 2023; 37:e22785. [PMID: 36794668 PMCID: PMC10561192 DOI: 10.1096/fj.202201413r] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 12/20/2022] [Accepted: 01/09/2023] [Indexed: 02/17/2023]
Abstract
The epigenome of stem cells occupies a critical interface between genes and environment, serving to regulate expression through modification by intrinsic and extrinsic factors. We hypothesized that aging and obesity, which represent major risk factors for a variety of diseases, synergistically modify the epigenome of adult adipose stem cells (ASCs). Using integrated RNA- and targeted bisulfite-sequencing in murine ASCs from lean and obese mice at 5- and 12-months of age, we identified global DNA hypomethylation with either aging or obesity, and a synergistic effect of aging combined with obesity. The transcriptome of ASCs in lean mice was relatively stable to the effects of age, but this was not true in obese mice. Functional pathway analyses identified a subset of genes with critical roles in progenitors and in diseases of obesity and aging. Specifically, Mapt, Nr3c2, App, and Ctnnb1 emerged as potential hypomethylated upstream regulators in both aging and obesity (AL vs. YL and AO vs. YO), and App, Ctnnb1, Hipk2, Id2, and Tp53 exhibited additional effects of aging in obese animals. Furthermore, Foxo3 and Ccnd1 were potential hypermethylated upstream regulators of healthy aging (AL vs. YL), and of the effects of obesity in young animals (YO vs. YL), suggesting that these factors could play a role in accelerated aging with obesity. Finally, we identified candidate driver genes that appeared recurrently in all analyses and comparisons undertaken. Further mechanistic studies are needed to validate the roles of these genes capable of priming ASCs for dysfunction in aging- and obesity-associated pathologies.
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Affiliation(s)
- Shaojun Xie
- Bioinformatics Core, Purdue University, 1022 Young Hall, 155 S. Grant Street, West Lafayette, IN 47907
| | - Sulbha Choudhari
- Bioinformatics Core, Purdue University, 1022 Young Hall, 155 S. Grant Street, West Lafayette, IN 47907
- Advanced Biomedical Computational Science, Bioinformatics and Computational Science, Frederick National Laboratory for Cancer Research, 8560 Progress Drive, Frederick, MD 2170
| | - Chia-Lung Wu
- Department of Orthopaedics and Rehabilitation, Center for Musculoskeletal Research, University of Rochester, Rochester, NY, 14611
| | - Karen Abramson
- Duke Molecular Physiology Institute, 300 North Duke Street, Durham, NC 27701
| | - David Corcoran
- Genomic Analysis and Bioinformatics Shared Resource, Duke Center for Genomic and Computational Biology, 101 Science Drive, Duke University Medical Center Box 3382, Durham, NC 27708
- Lineberger Bioinformatics Core, 5200 Marsico Hall, University of North Carolina-Chapel Hill, Chapel Hill, NC 27516
| | - Simon G. Gregory
- Duke Molecular Physiology Institute, 300 North Duke Street, Durham, NC 27701
- Department of Neurology, Duke University School of Medicine, 311 Research Drive, Durham, NC 27710
| | - Jyothi Thimmapuram
- Bioinformatics Core, Purdue University, 1022 Young Hall, 155 S. Grant Street, West Lafayette, IN 47907
| | - Farshid Guilak
- Department of Orthopaedic Surgery, Washington University in St. Louis, 4515 McKinley Ave., St. Louis, MO 63110
- Shriners Hospitals for Children – St. Louis, 4400 Clayton Ave, St. Louis Missouri 63110
| | - Dianne Little
- Departments of Basic Medical Sciences and Biomedical Engineering, Purdue University, 2186 Lynn Hall, 625 Harrison St, West Lafayette, IN 47907-2026
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Qiu Q, yang L, Feng Y, Zhu Z, Li N, Zheng L, Sun Y, Pan C, Qiu H, Cui X, He W, Wang F, Yi Y, Tang M, Yang Z, Yang Y, Li Z, Chen L, Hu Y. HDAC I/IIb selective inhibitor Purinostat Mesylate combined with GLS1 inhibition effectively eliminates CML stem cells. Bioact Mater 2023; 21:483-498. [PMID: 36185739 PMCID: PMC9486186 DOI: 10.1016/j.bioactmat.2022.08.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 08/01/2022] [Accepted: 08/06/2022] [Indexed: 11/25/2022] Open
Abstract
Purinostat Mesylate (PM) is a novel highly selective and active HDAC I/IIb inhibitor, and the injectable formulation of PM (PMF) based on the compound prescription containing cyclodextrin completely can overcome PM's poor solubility and improves its stability and pharmacokinetic properties. Here, we showed that PM effectively repressed the survival of Ph+ leukemia cells and CD34+ leukemia cells from CML patients in vitro. In vivo studies demonstrated that PMF significantly prevented BCR-ABL(T315I) induced CML progression by restraining leukemia stem cells (LSCs), which are insensitive to chemotherapy and responsible for CML relapse. Mechanism studies revealed that targeting HDAC I/IIb repressed several important factors for LSCs survival including c-Myc, β-Catenin, E2f, Ezh2, Alox5, and mTOR, as well as interrupted some critical biologic processes. Additionally, PMF increased glutamate metabolism in LSCs by increasing GLS1. The combination of PMF and glutaminase inhibitor BPTES synergistically eradicated LSCs by altering multiple key proteins and signaling pathways which are critical for LSC survival and self-renewal. Overall, our findings represent a new therapeutic strategy for eliminating LSCs by targeting HDAC I/IIb and glutaminolysis, which potentially provides a guidance for PMF clinical trials in the future for TKI resistance CML patients.
PM is a novel HDACI/IIb inhibitor with better selectivity and inhibitory activity than currently marketed HDAC inhibitors. PMF completely overcomes the problem of PM's poor solubility, and improved PM stability and pharmacokinetic properties. PMF effectively inhibits disease progression and abrogates leukemia stem cells survival in TKI-resistant CML mouse model. Simultaneous targeting of I/IIb HDACs and glutaminolysis could sufficiently eradicated LSCs in the mouse model.
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28
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Ma J, Huang A, Yan K, Li Y, Sun X, Joehanes R, Huan T, Levy D, Liu C. Blood transcriptomic biomarkers of alcohol consumption and cardiovascular disease risk factors: the Framingham Heart Study. Hum Mol Genet 2023; 32:649-658. [PMID: 36130209 PMCID: PMC9896471 DOI: 10.1093/hmg/ddac237] [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: 05/11/2022] [Revised: 08/19/2022] [Accepted: 09/15/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The relations of alcohol consumption and gene expression remain to be elucidated. MATERIALS AND METHODS We examined cross-sectional associations between alcohol consumption and whole blood derived gene expression levels and between alcohol-associated genes and obesity, hypertension, and diabetes in 5531 Framingham Heart Study (FHS) participants. RESULTS We identified 25 alcohol-associated genes. We further showed cross-sectional associations of 16 alcohol-associated genes with obesity, nine genes with hypertension, and eight genes with diabetes at P < 0.002. For example, we observed decreased expression of PROK2 (β = -0.0018; 95%CI: -0.0021, -0.0007; P = 6.5e - 5) and PAX5 (β = -0.0014; 95%CI: -0.0021, -0.0007; P = 6.5e - 5) per 1 g/day increase in alcohol consumption. Consistent with our previous observation on the inverse association of alcohol consumption with obesity and positive association of alcohol consumption with hypertension, we found that PROK2 was positively associated with obesity (OR = 1.42; 95%CI: 1.17, 1.72; P = 4.5e - 4) and PAX5 was negatively associated with hypertension (OR = 0.73; 95%CI: 0.59, 0.89; P = 1.6e - 3). We also observed that alcohol consumption was positively associated with expression of ABCA13 (β = 0.0012; 95%CI: 0.0007, 0.0017; P = 1.3e - 6) and ABCA13 was positively associated with diabetes (OR = 2.57; 95%CI: 1.73, 3.84; P = 3.5e - 06); this finding, however, was inconsistent with our observation of an inverse association between alcohol consumption and diabetes. CONCLUSIONS We showed strong cross-sectional associations between alcohol consumption and expression levels of 25 genes in FHS participants. Nonetheless, complex relationships exist between alcohol-associated genes and CVD risk factors.
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Affiliation(s)
- Jiantao Ma
- Division of Nutrition Epidemiology and Data Science, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA 02111, USA
- Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Allen Huang
- Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA 02142, USA
| | - Kaiyu Yan
- Department of Biostatistics, Boston University, Boston, MA 02118, USA
| | - Yi Li
- Department of Biostatistics, Boston University, Boston, MA 02118, USA
| | - Xianbang Sun
- Department of Biostatistics, Boston University, Boston, MA 02118, USA
| | - Roby Joehanes
- Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Tianxiao Huan
- Department of Ophthalmology and Visual Sciences, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Daniel Levy
- Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Boston University’s and National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA 01702, USA
| | - Chunyu Liu
- Department of Biostatistics, Boston University, Boston, MA 02118, USA
- Boston University’s and National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA 01702, USA
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29
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Suman S, Kumar S, Kallakury BVS, Moon BH, Angdisen J, Datta K, Fornace AJ. Predominant contribution of the dose received from constituent heavy-ions in the induction of gastrointestinal tumorigenesis after simulated space radiation exposure. RADIATION AND ENVIRONMENTAL BIOPHYSICS 2022; 61:631-637. [PMID: 36167896 DOI: 10.1007/s00411-022-00997-z] [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: 04/12/2022] [Accepted: 09/19/2022] [Indexed: 06/16/2023]
Abstract
Gastrointestinal (GI) cancer risk among astronauts after encountering galactic cosmic radiation (GCR) is predicted to exceed safe permissible limits in long duration deep-space missions. Current predictions are based on relative biological effectiveness (RBE) values derived from in-vivo studies using single-ion beams, while GCR is essentially a mixed radiation field composed of protons (H), helium (He), and heavy ions. Therefore, a sequentially delivered proton (H) → Helium (He) → Oxygen (O) → Silicon (Si) beam was designed to simulate simplified-mixed-field GCR (Smf-GCR), and Apc1638N/+ mice were total-body irradiated to sham or γ (157Cs) or Smf-GCR followed by assessment of GI-tumorigenesis at 150 days post-exposure. Further, GI-tumor data from equivalent doses of heavy-ions (i.e., 0.05 Gy of O and Si) in 0.5 Gy of Smf-GCR were compared to understand the contributions of heavy-ions in GI-tumorigenesis. The Smf-GCR-induced tumor and carcinoma count were significantly greater than γ-rays, and male preponderance for GI-tumorigenesis was consistent with our earlier findings. Comparison of tumor data from Smf-GCR and equivalent doses of heavy ions revealed an association between higher GI-tumorigenesis where dose received from heavy-ions contributed to > 95% of the total GI-tumorigenic effect observed after Smf-GCR. This study provides the first experimental evidence that cancer risk after GCR exposure could largely depend on doses received from constituent heavy-ions.
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Affiliation(s)
- Shubhankar Suman
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Research Building, Room E504, 3970 Reservoir Rd., NW, Washington, DC, 20057, USA.
| | - Santosh Kumar
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Research Building, Room E504, 3970 Reservoir Rd., NW, Washington, DC, 20057, USA
| | - Bhaskar V S Kallakury
- Department of Pathology, Georgetown University Medical Center, Washington, DC, 20057, USA
| | - Bo-Hyun Moon
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Research Building, Room E504, 3970 Reservoir Rd., NW, Washington, DC, 20057, USA
| | - Jerry Angdisen
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Research Building, Room E504, 3970 Reservoir Rd., NW, Washington, DC, 20057, USA
| | - Kamal Datta
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Research Building, Room E504, 3970 Reservoir Rd., NW, Washington, DC, 20057, USA
- Department of Biochemistry and Molecular and Cellular Biology and Department of Oncology, Georgetown University Medical Center, Washington, DC, 20057, USA
| | - Albert J Fornace
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Research Building, Room E504, 3970 Reservoir Rd., NW, Washington, DC, 20057, USA
- Department of Biochemistry and Molecular and Cellular Biology and Department of Oncology, Georgetown University Medical Center, Washington, DC, 20057, USA
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Sun J, Yang M, Zhao W, Wang F, Yang L, Tan C, Hu T, Zhu H, Zhao G. Research progress on the relationship between the TOR signaling pathway regulator, epigenetics, and tumor development. Front Genet 2022; 13:1006936. [PMID: 36212146 PMCID: PMC9539685 DOI: 10.3389/fgene.2022.1006936] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 08/31/2022] [Indexed: 11/16/2022] Open
Abstract
Almost all cellular activities depend on protein folding, signaling complex assembly/disassembly, and epigenetic regulation. One of the most important regulatory mechanisms responsible for controlling these cellular processes is dynamic protein phosphorylation/dephosphorylation. Alterations in phosphorylation networks have major consequences in the form of disorders, including cancer. Many signaling cascades, including the target of rapamycin (TOR) signaling, are important participants in the cell cycle, and dysregulation in their phosphorylation/dephosphorylation status has been linked to malignancies. As a TOR signaling regulator, protein phosphatase 2A (PP2A) is responsible for most of the phosphatase activities inside the cells. On the other hand, TOR signaling pathway regulator (TIPRL) is an essential PP2A inhibitory protein. Many other physiological roles have also been suggested for TIPRL, such as modulation of TOR pathways, apoptosis, and cell proliferation. It is also reported that TIPRL was increased in various carcinomas, including non-small-cell lung carcinoma (NSCLC) and hepatocellular carcinomas (HCC). Considering the function of PP2A as a tumor suppressor and also the effect of the TIPRL/PP2A axis on apoptosis and proliferation of cancer cells, this review aims to provide a complete view of the role of TIPRL in cancer development in addition to describing TIPRL/PP2A axis and its epigenetic regulation.
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Affiliation(s)
- Jiaen Sun
- School of Medicine, Ningbo University, Ningbo, Zhejiang, China
- Department of Thoracic Surgery, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
| | - Minglei Yang
- School of Medicine, Ningbo University, Ningbo, Zhejiang, China
- Department of Thoracic Surgery, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
| | - Weidi Zhao
- School of Medicine, Ningbo University, Ningbo, Zhejiang, China
- Department of Thoracic Surgery, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
| | - Fajiu Wang
- Department of Thoracic Surgery, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
| | - Liangwei Yang
- Department of Thoracic Surgery, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
| | - Chuntao Tan
- Department of Cardiac and Vascular Surgery, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
| | - Tianjun Hu
- Department of Thoracic Surgery, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
| | - Huangkai Zhu
- School of Medicine, Ningbo University, Ningbo, Zhejiang, China
- Department of Thoracic Surgery, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
- *Correspondence: Huangkai Zhu, ; Guofang Zhao,
| | - Guofang Zhao
- School of Medicine, Ningbo University, Ningbo, Zhejiang, China
- Department of Thoracic Surgery, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
- *Correspondence: Huangkai Zhu, ; Guofang Zhao,
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31
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F. V, V. D. P, C. M, M. LI, C. D, G. P, D. C, A. T, M. G, S. DF, M. T, V. V, G. S. Targeting epigenetic alterations in cancer stem cells. FRONTIERS IN MOLECULAR MEDICINE 2022; 2:1011882. [PMID: 39086963 PMCID: PMC11285701 DOI: 10.3389/fmmed.2022.1011882] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 09/08/2022] [Indexed: 08/02/2024]
Abstract
Oncogenes or tumor suppressor genes are rarely mutated in several pediatric tumors and some early stage adult cancers. This suggests that an aberrant epigenetic reprogramming may crucially affect the tumorigenesis of these tumors. Compelling evidence support the hypothesis that cancer stem cells (CSCs), a cell subpopulation within the tumor bulk characterized by self-renewal capacity, metastatic potential and chemo-resistance, may derive from normal stem cells (NSCs) upon an epigenetic deregulation. Thus, a better understanding of the specific epigenetic alterations driving the transformation from NSCs into CSCs may help to identify efficacious treatments to target this aggressive subpopulation. Moreover, deepening the knowledge about these alterations may represent the framework to design novel therapeutic approaches also in the field of regenerative medicine in which bioengineering of NSCs has been evaluated. Here, we provide a broad overview about: 1) the role of aberrant epigenetic modifications contributing to CSC initiation, formation and maintenance, 2) the epigenetic inhibitors in clinical trial able to specifically target the CSC subpopulation, and 3) epigenetic drugs and stem cells used in regenerative medicine for cancer and diseases.
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Affiliation(s)
- Verona F.
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Pantina V. D.
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, Palermo, Italy
| | - Modica C.
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, Palermo, Italy
| | - Lo Iacono M.
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - D’Accardo C.
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Porcelli G.
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Cricchio D.
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, Palermo, Italy
| | - Turdo A.
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Gaggianesi M.
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, Palermo, Italy
| | - Di Franco S.
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, Palermo, Italy
| | - Todaro M.
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Veschi V.
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, Palermo, Italy
| | - Stassi G.
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, Palermo, Italy
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Luo M, Bao L, Chen Y, Xue Y, Wang Y, Zhang B, Wang C, Corley CD, McDonald JG, Kumar A, Xing C, Fang Y, Nelson ER, Wang JE, Wang Y, Luo W. ZMYND8 is a master regulator of 27-hydroxycholesterol that promotes tumorigenicity of breast cancer stem cells. SCIENCE ADVANCES 2022; 8:eabn5295. [PMID: 35857506 PMCID: PMC9286501 DOI: 10.1126/sciadv.abn5295] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 06/02/2022] [Indexed: 06/15/2023]
Abstract
27-Hydroxycholesterol (27-HC) is the most abundant oxysterol that increases the risk of breast cancer progression. However, little is known about epigenetic regulation of 27-HC metabolism and its role in breast tumor initiation. Using genetic mouse mammary tumor and human breast cancer models, we showed here that the histone reader ZMYND8 was selectively expressed in breast cancer stem cells (BCSCs) and promoted epithelial-mesenchymal transition (EMT), BCSC maintenance and self-renewal, and oncogenic transformation through its epigenetic functions, leading to breast tumor initiation. Mechanistically, ZMYND8 was a master transcriptional regulator of 27-HC metabolism. It increased cholesterol biosynthesis and oxidation but blocked cholesterol efflux and 27-HC catabolism, leading to accumulation of 27-HC in BCSCs. Consequently, 27-HC promoted EMT, oncogenic transformation, and tumor initiation through activation of liver X receptor. These findings reveal that ZMYND8 is an epigenetic booster that drives breast tumor initiation through metabolic reprogramming.
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Affiliation(s)
- Maowu Luo
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Lei Bao
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Yan Chen
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Yuanyuan Xue
- Children’s Medical Center Research Institute, UT Southwestern Medical Center, Dallas, TX, USA
| | - Yong Wang
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Bo Zhang
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Chenliang Wang
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Chase D. Corley
- Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX, USA
| | - Jeffrey G. McDonald
- Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX, USA
- Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX, USA
| | - Ashwani Kumar
- Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX, USA
| | - Chao Xing
- Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX, USA
- Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX, USA
- Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, TX, USA
| | - Yisheng Fang
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Erik R. Nelson
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL, USA
- Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL, USA
- Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Jennifer E. Wang
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Yingfei Wang
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
- Department of Neurology, UT Southwestern Medical Center, Dallas, TX, USA
- Peter O’Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA
| | - Weibo Luo
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
- Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX, USA
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33
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Genetically modified mice for research on human diseases: A triumph for Biotechnology or a work in progress? THE EUROBIOTECH JOURNAL 2022. [DOI: 10.2478/ebtj-2022-0008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/06/2022] Open
Abstract
Abstract
Genetically modified mice are engineered as models for human diseases. These mouse models include inbred strains, mutants, gene knockouts, gene knockins, and ‘humanized’ mice. Each mouse model is engineered to mimic a specific disease based on a theory of the genetic basis of that disease. For example, to test the amyloid theory of Alzheimer’s disease, mice with amyloid precursor protein genes are engineered, and to test the tau theory, mice with tau genes are engineered. This paper discusses the importance of mouse models in basic research, drug discovery, and translational research, and examines the question of how to define the “best” mouse model of a disease. The critiques of animal models and the caveats in translating the results from animal models to the treatment of human disease are discussed. Since many diseases are heritable, multigenic, age-related and experience-dependent, resulting from multiple gene-gene and gene-environment interactions, it will be essential to develop mouse models that reflect these genetic, epigenetic and environmental factors from a developmental perspective. Such models would provide further insight into disease emergence, progression and the ability to model two-hit and multi-hit theories of disease. The summary examines the biotechnology for creating genetically modified mice which reflect these factors and how they might be used to discover new treatments for complex human diseases such as cancers, neurodevelopmental and neurodegenerative diseases.
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34
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Casado-García A, Isidro-Hernández M, Oak N, Mayado A, Mann-Ran C, Raboso-Gallego J, Alemán-Arteaga S, Buhles A, Sterker D, Sánchez EG, Martínez-Cano J, Blanco O, Orfao A, Alonso-López D, De Las Rivas J, Riesco S, Prieto-Matos P, González-Murillo Á, García Criado FJ, García Cenador MB, Radimerski T, Ramírez-Orellana M, Cobaleda C, Yang JJ, Vicente-Dueñas C, Weiss A, Nichols KE, Sánchez-García I. Transient Inhibition of the JAK/STAT Pathway Prevents B-ALL Development in Genetically Predisposed Mice. Cancer Res 2022; 82:1098-1109. [PMID: 35131871 PMCID: PMC9359729 DOI: 10.1158/0008-5472.can-21-3386] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 12/14/2021] [Accepted: 01/24/2022] [Indexed: 01/07/2023]
Abstract
Preventing development of childhood B-cell acute lymphoblastic leukemia (B-ALL), a disease with devastating effects, is a longstanding and unsolved challenge. Heterozygous germline alterations in the PAX5 gene can lead to B-ALL upon accumulation of secondary mutations affecting the JAK/STAT signaling pathway. Preclinical studies have shown that this malignant transformation occurs only under immune stress such as exposure to infectious pathogens. Here we show in Pax5+/- mice that transient, early-life administration of clinically relevant doses of ruxolitinib, a JAK1/2 inhibitor, significantly mitigates the risk of B-ALL following exposure to infection; 1 of 29 animals treated with ruxolitinib developed B-ALL versus 8 of 34 untreated mice. Ruxolitinib treatment preferentially targeted Pax5+/- versus wild-type B-cell progenitors and exerted unique effects on the Pax5+/- B-cell progenitor transcriptional program. These findings provide the first in vivo evidence for a potential strategy to prevent B-ALL development. SIGNIFICANCE JAK/STAT inhibition suppresses tumorigenesis in a B-ALL-susceptible mouse model, presenting a novel approach to prevent B-ALL onset.
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Affiliation(s)
- Ana Casado-García
- Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC-USAL, Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | - Marta Isidro-Hernández
- Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC-USAL, Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | - Ninad Oak
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Andrea Mayado
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Servicio de Citometría, Departamento de Medicina, Biomedical Research Networking Centre on Cancer CIBER-CIBERONC (CB16/12/00400), Institute of Health Carlos III, and Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Salamanca, Spain
| | - Christine Mann-Ran
- Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland
| | - Javier Raboso-Gallego
- Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC-USAL, Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | - Silvia Alemán-Arteaga
- Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC-USAL, Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | - Alexandra Buhles
- Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland
| | - Dario Sterker
- Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland
| | - Elena G. Sánchez
- Department of Pediatric Hematology and Oncology, Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, Madrid, Spain
| | - Jorge Martínez-Cano
- Immune system development and function Unit, Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas -Universidad Autónoma de Madrid), Madrid, Spain
| | - Oscar Blanco
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Departamento de Anatomía Patológica, Universidad de Salamanca, Salamanca, Spain
| | - Alberto Orfao
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Servicio de Citometría, Departamento de Medicina, Biomedical Research Networking Centre on Cancer CIBER-CIBERONC (CB16/12/00400), Institute of Health Carlos III, and Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Salamanca, Spain
| | - Diego Alonso-López
- Bioinformatics Unit, Cancer Research Center (CSIC-USAL), Salamanca, Spain
| | - Javier De Las Rivas
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Bioinformatics and Functional Genomics Research Group, Cancer Research Center (CSIC-USAL), Salamanca, Spain
| | - Susana Riesco
- Department of Pediatrics, Hospital Universitario de Salamanca, Paseo de San Vicente, 58–182, Salamanca, Spain
| | - Pablo Prieto-Matos
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Department of Pediatrics, Hospital Universitario de Salamanca, Paseo de San Vicente, 58–182, Salamanca, Spain
| | - África González-Murillo
- Department of Pediatric Hematology and Oncology, Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, Madrid, Spain
| | - Francisco Javier García Criado
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain
| | - María Begoña García Cenador
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain
| | - Thomas Radimerski
- Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland
| | - Manuel Ramírez-Orellana
- Department of Pediatric Hematology and Oncology, Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, Madrid, Spain
| | - César Cobaleda
- Immune system development and function Unit, Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas -Universidad Autónoma de Madrid), Madrid, Spain
| | - Jun J. Yang
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Carolina Vicente-Dueñas
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Department of Pediatrics, Hospital Universitario de Salamanca, Paseo de San Vicente, 58–182, Salamanca, Spain
| | - Andreas Weiss
- Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland
| | - Kim E. Nichols
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Isidro Sánchez-García
- Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC-USAL, Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
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35
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Liu D, Li H, Dong H, Qu M, Yang L, Chen L, Li Y, Wang H, He Y. Spatial Multiomics Analysis Reveals Only Minor Genetic and Epigenetic Changes in Human Liver Cancer Stem-Like Cells Compared With Other Tumor Parenchymal Cells. Front Cell Dev Biol 2022; 10:810687. [PMID: 35223840 PMCID: PMC8863946 DOI: 10.3389/fcell.2022.810687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 01/17/2022] [Indexed: 11/13/2022] Open
Abstract
Cancer stem cells (CSCs) usually account for a very small tumor cell population but play pivotal roles in human cancer development and recurrence. A fundamental question in cancer biology is what genetic and epigenetic changes occur in CSCs. Here we show that the in-situ global levels of DNA cytosine modifications, including 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) and 5-formylcytosine (5fC), are similar between liver cancer stem-like (LCSL) cells and paratumor liver cells of liver cancer patients. We then developed a robust method combining immunohistochemistry, laser capture microdissection and genome sequencing with ultra-low-input cells (CIL-seq) to study the detailed genetic and DNA methylation changes in human LCSL cells. We first used clinical samples of mixed hepatocellular carcinoma-cholangiocarcinoma (HCC-CCA) with stem cell features to investigate human LCSL cells. The CIL-seq analysis of HCC-CCA and HCC patients showed that LCSL cells had strong spatial genetic and epigenetic heterogeneity. More interestingly, although the LCSL cells had some potential key changes in their genome, they had substantially fewer somatic single nucleotide variants (SNVs), copy number alterations (CNAs) and differentially methylated regions than other tumor parenchymal cells. The cluster analysis of SNVs, CNAs, DNA methylation patterns and spatial transcriptomes all clearly showed that the LCSL cells were clustered with the paratumor liver cells. Thus, spatial multiomics analysis showed that LCSL cells had only minor genetic and epigenetic changes compared with other tumor parenchymal cells. Targeting key changes in CSCs, not just changes in bulk tumor cells, should be more effective for human cancer therapy.
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Affiliation(s)
- Dan Liu
- Model Animal Research Center, Medical School, Nanjing University, Nanjing, China.,Molecular Pathology Laboratory, National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Hong Li
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Hui Dong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Mincheng Qu
- Model Animal Research Center, Medical School, Nanjing University, Nanjing, China.,Molecular Pathology Laboratory, National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Liguang Yang
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Lina Chen
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yixue Li
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Hongyang Wang
- Model Animal Research Center, Medical School, Nanjing University, Nanjing, China.,National Center for Liver Cancer and International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Shanghai, China
| | - Yufei He
- Molecular Pathology Laboratory, National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
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36
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Tinsley SL, Allen-Petersen BL. PP2A and cancer epigenetics: a therapeutic opportunity waiting to happen. NAR Cancer 2022; 4:zcac002. [PMID: 35118387 PMCID: PMC8807117 DOI: 10.1093/narcan/zcac002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 12/08/2021] [Accepted: 01/10/2022] [Indexed: 12/13/2022] Open
Abstract
The epigenetic state of chromatin is altered by regulators which influence gene expression in response to environmental stimuli. While several post-translational modifications contribute to chromatin accessibility and transcriptional programs, our understanding of the role that specific phosphorylation sites play is limited. In cancer, kinases and phosphatases are commonly deregulated resulting in increased oncogenic signaling and loss of epigenetic regulation. Aberrant epigenetic states are known to promote cellular plasticity and the development of therapeutic resistance in many cancer types, highlighting the importance of these mechanisms to cancer cell phenotypes. Protein Phosphatase 2A (PP2A) is a heterotrimeric holoenzyme that targets a diverse array of cellular proteins. The composition of the PP2A complex influences its cellular targets and activity. For this reason, PP2A can be tumor suppressive or oncogenic depending on cellular context. Understanding the nuances of PP2A regulation and its effect on epigenetic alterations can lead to new therapeutic avenues that afford more specificity and contribute to the growth of personalized medicine in the oncology field. In this review, we summarize the known PP2A-regulated substrates and potential phosphorylation sites that contribute to cancer cell epigenetics and possible strategies to therapeutically leverage this phosphatase to suppress tumor growth.
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Affiliation(s)
- Samantha L Tinsley
- Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA
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Yao Y, Wen Q, Zhang T, Yu C, Chan KM, Gan H. Advances in Approaches to Study Chromatin-Mediated Epigenetic Memory. ACS Synth Biol 2022; 11:16-25. [PMID: 34965084 DOI: 10.1021/acssynbio.1c00394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Chromatin structure contains critical epigenetic information in various forms, such as histone post-translational modifications (PTMs). The deposition of certain histone PTMs can remodel the chromatin structure, resulting in gene expression alteration. The epigenetic information carried by histone PTMs could be inherited by daughter cells to maintain the gene expression status. Recently, studies revealed that several conserved replisome proteins regulate the recycling of parental histones carrying epigenetic information in Saccharomyces cerevisiae. Hence, the proper recycling and deposition of parental histones onto newly synthesized DNA strands is presumed to be essential for epigenetic inheritance. Here, we first reviewed the fundamental mechanisms of epigenetic modification establishment and maintenance discovered within fungal models. Next, we discussed the functions of parental histone chaperones and the potential impacts of the parental histone recycling process on heterochromatin-mediated transcriptional silencing inheritance. Subsequently, we summarized novel synthetic biology approaches developed to analyze individual epigenetic components during epigenetic inheritance in fungal and mammalian systems. These newly emerged research paradigms enable us to dissect epigenetic systems in a bottom-up manner. Furthermore, we highlighted the approaches developed in this emerging field and discussed the potential applications of these engineered regulators to building synthetic epigenetic systems.
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Affiliation(s)
- Yuan Yao
- Shenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Qing Wen
- Shenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Tianjun Zhang
- Shenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
- Department of Molecular and Biomedical Science, School of Biological Sciences, The University of Adelaide, Adelaide, SA 5005, Australia
| | - Chuanhe Yu
- The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, United States
| | - Kui Ming Chan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR 999077, China
- Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen 518172, China
| | - Haiyun Gan
- Shenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
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38
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Schmidt JA, Hornhardt S, Erdmann F, Sánchez-García I, Fischer U, Schüz J, Ziegelberger G. Risk Factors for Childhood Leukemia: Radiation and Beyond. Front Public Health 2021; 9:805757. [PMID: 35004601 PMCID: PMC8739478 DOI: 10.3389/fpubh.2021.805757] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 12/06/2021] [Indexed: 12/20/2022] Open
Abstract
Childhood leukemia (CL) is undoubtedly caused by a multifactorial process with genetic as well as environmental factors playing a role. But in spite of several efforts in a variety of scientific fields, the causes of the disease and the interplay of possible risk factors are still poorly understood. To push forward the research on the causes of CL, the German Federal Office for Radiation Protection has been organizing recurring international workshops since 2008 every two to three years. In November 2019 the 6th International Workshop on the Causes of CL was held in Freising and brought together experts from diverse disciplines. The workshop was divided into two main parts focusing on genetic and environmental risk factors, respectively. Two additional special sessions addressed the influence of natural background radiation on the risk of CL and the progress in the development of mouse models used for experimental studies on acute lymphoblastic leukemia, the most common form of leukemia worldwide. The workshop presentations highlighted the role of infections as environmental risk factor for CL, specifically for acute lymphoblastic leukemia. Major support comes from two mouse models, the Pax5+/- and Sca1-ETV6-RUNX1 mouse model, one of the major achievements made in the last years. Mice of both predisposed models only develop leukemia when exposed to common infections. These results emphasize the impact of gene-environment-interactions on the development of CL and warrant further investigation of such interactions - especially because genetic predisposition is detected with increasing frequency in CL. This article summarizes the workshop presentations and discusses the results in the context of the international literature.
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Affiliation(s)
- Janine-Alison Schmidt
- Department of Effects and Risks of Ionizing and Non-ionizing Radiation, Federal Office for Radiation Protection (BfS), Neuherberg, Germany
| | - Sabine Hornhardt
- Department of Effects and Risks of Ionizing and Non-ionizing Radiation, Federal Office for Radiation Protection (BfS), Neuherberg, Germany
| | - Friederike Erdmann
- Division of Childhood Cancer Epidemiology, Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
- Environment and Lifestyle Epidemiology Branch, International Agency for Research on Cancer, World Health Organization (IARC/WHO), Lyon, France
| | - Isidro Sánchez-García
- Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Salamanca, Spain
| | - Ute Fischer
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Joachim Schüz
- Environment and Lifestyle Epidemiology Branch, International Agency for Research on Cancer, World Health Organization (IARC/WHO), Lyon, France
| | - Gunde Ziegelberger
- Department of Effects and Risks of Ionizing and Non-ionizing Radiation, Federal Office for Radiation Protection (BfS), Neuherberg, Germany
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Lenz G, Onzi GR, Lenz LS, Buss JH, Santos JAF, Begnini KR. The Origins of Phenotypic Heterogeneity in Cancer. Cancer Res 2021; 82:3-11. [PMID: 34785576 DOI: 10.1158/0008-5472.can-21-1940] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 09/14/2021] [Accepted: 11/10/2021] [Indexed: 11/16/2022]
Abstract
Heterogeneity is a pervasive feature of cancer, and understanding the sources and regulatory mechanisms underlying heterogeneity could provide key insights to help improve the diagnosis and treatment of cancer. In this review, we discuss the origin of heterogeneity in the phenotype of individual cancer cells. Genotype-phenotype (G-P) maps are widely used in evolutionary biology to represent the complex interactions of genes and the environment that lead to phenotypes that impact fitness. Here, we present the rationale of an extended G-P (eG-P) map with a cone structure in cancer. The eG-P cone is formed by cells that are similar at the genome layer but gradually increase variability in the epigenome, transcriptome, proteome, metabolome and signalome layers to produce large variability at the phenome layer. Experimental evidence from single-cell -omics analyses supporting the cancer eG-P cone concept is presented, and the impact of epimutations and the interaction of cancer and tumor microenvironmental eG-P cones are integrated with the current understanding of cancer biology. The eG-P cone concept uncovers potential therapeutic strategies to reduce cancer evolution and improve cancer treatment. More methods to study phenotypes in single cells will be key to better understand cancer cell fitness in tumor biology and therapeutics.
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Wang Z. Mechanisms of the synergistic lung tumorigenic effect of arsenic and benzo(a)pyrene combined- exposure. Semin Cancer Biol 2021; 76:156-162. [PMID: 33971262 PMCID: PMC9000133 DOI: 10.1016/j.semcancer.2021.05.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 05/01/2021] [Indexed: 12/20/2022]
Abstract
Humans are often exposed to mixtures of environmental pollutants especially environmental chemical carcinogens, representing a significant environmental health issue. However, our understanding on the carcinogenic effects and mechanisms of environmental carcinogen mixture exposures is limited and mostly relies on the findings from studying individual chemical carcinogens. Both arsenic and benzo(a)pyrene (BaP) are among the most common environmental carcinogens causing lung cancer and other types of cancer in humans. Millions of people are exposed to arsenic via consuming arsenic-contaminated drinking water and even more people are exposed to BaP via cigarette smoking and consuming BaP-contaminated food. Thus arsenic and BaP combined-exposure in humans is common. Previous epidemiology studies indicated that arsenic-exposed people who were cigarette smokers had significantly higher lung cancer risk than those who were non-smokers. Since BaP is one of the major carcinogens in cigarette smoke, it has been speculated that arsenic and BaP combined-exposure may play important roles in the increased lung cancer risk observed in arsenic-exposed cigarette smokers. In this review, we summarize important findings and inconsistencies about the co-carcinogenic effects and underlying mechanisms of arsenic and BaP combined-exposure and propose new areas for future studies. A clear understanding on the mechanism of co-carcinogenic effects of arsenic and BaP combined exposure may identify novel targets to more efficiently treat and prevent lung cancer resulting from arsenic and BaP combined-exposure.
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Affiliation(s)
- Zhishan Wang
- Division of Cancer Biology, Department of Medicine, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, 44109, USA.
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41
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Maurya SS. Role of Enhancers in Development and Diseases. EPIGENOMES 2021; 5:epigenomes5040021. [PMID: 34968246 PMCID: PMC8715447 DOI: 10.3390/epigenomes5040021] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 09/21/2021] [Accepted: 09/28/2021] [Indexed: 12/26/2022] Open
Abstract
Enhancers are cis-regulatory elements containing short DNA sequences that serve as binding sites for pioneer/regulatory transcription factors, thus orchestrating the regulation of genes critical for lineage determination. The activity of enhancer elements is believed to be determined by transcription factor binding, thus determining the cell state identity during development. Precise spatio-temporal control of the transcriptome during lineage specification requires the coordinated binding of lineage-specific transcription factors to enhancers. Thus, enhancers are the primary determinants of cell identity. Numerous studies have explored the role and mechanism of enhancers during development and disease, and various basic questions related to the functions and mechanisms of enhancers have not yet been fully answered. In this review, we discuss the recently published literature regarding the roles of enhancers, which are critical for various biological processes governing development. Furthermore, we also highlight that altered enhancer landscapes provide an essential context to understand the etiologies and mechanisms behind numerous complex human diseases, providing new avenues for effective enhancer-based therapeutic interventions.
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Affiliation(s)
- Shailendra S Maurya
- Department of Pediatrics, Division of Pediatric Hematology and Oncology, Department of Developmental Biology, School of Medicine, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, MO 63110, USA
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Cobaleda C, Vicente-Dueñas C, Sanchez-Garcia I. Infectious triggers and novel therapeutic opportunities in childhood B cell leukaemia. Nat Rev Immunol 2021; 21:570-581. [PMID: 33558682 DOI: 10.1038/s41577-021-00505-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/08/2021] [Indexed: 01/30/2023]
Abstract
B cell acute lymphoblastic leukaemia (B-ALL) is the most common form of childhood cancer. Although treatment has advanced remarkably in the past 50 years, it still fails in ~20% of patients. Recent studies revealed that more than 5% of healthy newborns carry preleukaemic clones that originate in utero, but only a small percentage of these carriers will progress to overt B-ALL. The drivers of progression are unclear, but B-ALL incidence seems to be increasing in parallel with the adoption of modern lifestyles. Emerging evidence shows that a major driver for the conversion from the preleukaemic state to the B-ALL state is exposure to immune stressors, such as infection. Here, we discuss our current understanding of the environmental triggers and genetic predispositions that may lead to B-ALL, highlighting lessons from epidemiology, the clinic and animal models, and identifying priority areas for future research.
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Affiliation(s)
- Cesar Cobaleda
- Immune System Development and Function Unit, Centro de Biología Molecular Severo Ochoa, CSIC and Universidad Autónoma de Madrid, Madrid, Spain.
| | | | - Isidro Sanchez-Garcia
- Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain. .,Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC and Universidad de Salamanca, Salamanca, Spain.
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43
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Keeping your options open: insights from Dppa2/4 into how epigenetic priming factors promote cell plasticity. Biochem Soc Trans 2021; 48:2891-2902. [PMID: 33336687 PMCID: PMC7752079 DOI: 10.1042/bst20200873] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/01/2020] [Accepted: 12/02/2020] [Indexed: 12/12/2022]
Abstract
The concept of cellular plasticity is particularly apt in early embryonic development, where there is a tug-of-war between the stability and flexibility of cell identity. This balance is controlled in part through epigenetic mechanisms. Epigenetic plasticity dictates how malleable cells are to change by adjusting the potential to initiate new transcriptional programmes. The higher the plasticity of a cell, the more readily it can adapt and change its identity in response to external stimuli such as differentiation cues. Epigenetic plasticity is regulated in part through the action of epigenetic priming factors which establish this permissive epigenetic landscape at genomic regulatory elements to enable future transcriptional changes. Recent studies on the DNA binding proteins Developmental Pluripotency Associated 2 and 4 (Dppa2/4) support their roles as epigenetic priming factors in facilitating cell fate transitions. Here, using Dppa2/4 as a case study, the concept of epigenetic plasticity and molecular mechanism of epigenetic priming factors will be explored. Understanding how epigenetic priming factors function is key not only to improve our understanding of the tight control of development, but also to give insights into how this goes awry in diseases of cell identity, such as cancer.
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He Y, Yu X, Zhang M, Guo W. Pan-cancer analysis of m 5C regulator genes reveals consistent epigenetic landscape changes in multiple cancers. World J Surg Oncol 2021; 19:224. [PMID: 34325709 PMCID: PMC8323224 DOI: 10.1186/s12957-021-02342-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 07/21/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND 5-Methylcytosine (m5C) is a reversible modification to both DNA and various cellular RNAs. However, its roles in developing human cancers are poorly understood, including the effects of mutant m5C regulators and the outcomes of modified nucleobases in RNAs. METHODS Based on The Cancer Genome Atlas (TCGA) database, we uncovered that mutations and copy number variations (CNVs) of m5C regulatory genes were significantly correlated across many cancer types. We then assessed the correlation between the expression of individual m5C regulators and the activity of related hallmark pathways of cancers. RESULTS After validating m5C regulators' expression based on their contributions to cancer development and progression, we observed their upregulation within tumor-specific processes. Notably, our research connected aberrant alterations to m5C regulatory genes with poor clinical outcomes among various tumors that may drive cancer pathogenesis and/or survival. CONCLUSION Our results offered strong evidence and clinical implications for the involvement of m5C regulators.
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Affiliation(s)
- Yuting He
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe Road, Zhengzhou, 450052, China.
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation At Henan Universities, Zhengzhou, 450052, China.
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, 450052, China.
| | - Xiao Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe Road, Zhengzhou, 450052, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation At Henan Universities, Zhengzhou, 450052, China
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, 450052, China
| | - Menggang Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe Road, Zhengzhou, 450052, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation At Henan Universities, Zhengzhou, 450052, China
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, 450052, China
| | - Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe Road, Zhengzhou, 450052, China.
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation At Henan Universities, Zhengzhou, 450052, China.
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, 450052, China.
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Rodríguez-Hernández G, Casado-García A, Isidro-Hernández M, Picard D, Raboso-Gallego J, Alemán-Arteaga S, Orfao A, Blanco O, Riesco S, Prieto-Matos P, García Criado FJ, García Cenador MB, Hock H, Enver T, Sanchez-Garcia I, Vicente-Dueñas C. The Second Oncogenic Hit Determines the Cell Fate of ETV6-RUNX1 Positive Leukemia. Front Cell Dev Biol 2021; 9:704591. [PMID: 34336858 PMCID: PMC8320889 DOI: 10.3389/fcell.2021.704591] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 06/18/2021] [Indexed: 12/27/2022] Open
Abstract
ETV6-RUNX1 is almost exclusively associated with childhood B-cell acute lymphoblastic leukemia (B-ALL), but the consequences of ETV6-RUNX1 expression on cell lineage decisions during B-cell leukemogenesis are completely unknown. Clinically silent ETV6-RUNX1 preleukemic clones are frequently found in neonatal cord blood, but few carriers develop B-ALL as a result of secondary genetic alterations. The understanding of the mechanisms underlying the first transforming steps could greatly advance the development of non-toxic prophylactic interventions. Using genetic lineage tracing, we examined the capacity of ETV6-RUNX1 to instruct a malignant phenotype in the hematopoietic lineage by cell-specific Cre-mediated activation of ETV6-RUNX1 from the endogenous Etv6 gene locus. Here we show that, while ETV6-RUNX1 has the propensity to trigger both T- and B-lymphoid malignancies, it is the second hit that determines tumor cell identity. To instigate leukemia, both oncogenic hits must place early in the development of hematopoietic/precursor cells, not in already committed B-cells. Depending on the nature of the second hit, the resulting B-ALLs presented distinct entities that were clearly separable based on their gene expression profiles. Our findings give a novel mechanistic insight into the early steps of ETV6-RUNX1+ B-ALL development and might have major implications for the potential development of ETV6-RUNX1+ B-ALL prevention strategies.
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Affiliation(s)
- Guillermo Rodríguez-Hernández
- Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas/Universidad de Salamanca, Salamanca, Spain.,Institute for Biomedical Research of Salamanca, Salamanca, Spain
| | - Ana Casado-García
- Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas/Universidad de Salamanca, Salamanca, Spain.,Institute for Biomedical Research of Salamanca, Salamanca, Spain
| | - Marta Isidro-Hernández
- Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas/Universidad de Salamanca, Salamanca, Spain.,Institute for Biomedical Research of Salamanca, Salamanca, Spain
| | - Daniel Picard
- Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Javier Raboso-Gallego
- Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas/Universidad de Salamanca, Salamanca, Spain.,Institute for Biomedical Research of Salamanca, Salamanca, Spain
| | - Silvia Alemán-Arteaga
- Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas/Universidad de Salamanca, Salamanca, Spain.,Institute for Biomedical Research of Salamanca, Salamanca, Spain
| | - Alberto Orfao
- Institute for Biomedical Research of Salamanca, Salamanca, Spain.,Servicio de Citometría, Departamento de Medicina, CIBERONC (CB16/12/00400), and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas/Universidad de Salamanca, Salamanca, Spain
| | - Oscar Blanco
- Institute for Biomedical Research of Salamanca, Salamanca, Spain.,Departamento de Anatomía Patológica, Universidad de Salamanca, Salamanca, Spain
| | - Susana Riesco
- Institute for Biomedical Research of Salamanca, Salamanca, Spain.,Department of Pediatrics, Hospital Universitario de Salamanca, Salamanca, Spain
| | - Pablo Prieto-Matos
- Institute for Biomedical Research of Salamanca, Salamanca, Spain.,Department of Pediatrics, Hospital Universitario de Salamanca, Salamanca, Spain
| | - Francisco Javier García Criado
- Institute for Biomedical Research of Salamanca, Salamanca, Spain.,Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain
| | - María Begoña García Cenador
- Institute for Biomedical Research of Salamanca, Salamanca, Spain.,Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain
| | - Hanno Hock
- Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, and Harvard Stem Cell Institute, Boston, MA, United States
| | - Tariq Enver
- Department of Cancer Biology, UCL Cancer Institute, University College London, London, United Kingdom
| | - Isidro Sanchez-Garcia
- Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas/Universidad de Salamanca, Salamanca, Spain.,Institute for Biomedical Research of Salamanca, Salamanca, Spain
| | - Carolina Vicente-Dueñas
- Institute for Biomedical Research of Salamanca, Salamanca, Spain.,Department of Pediatrics, Hospital Universitario de Salamanca, Salamanca, Spain
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Rodriguez FD, Coveñas R. Biochemical Mechanisms Associating Alcohol Use Disorders with Cancers. Cancers (Basel) 2021; 13:cancers13143548. [PMID: 34298760 PMCID: PMC8306032 DOI: 10.3390/cancers13143548] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/01/2021] [Accepted: 07/14/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Of all yearly deaths attributable to alcohol consumption globally, approximately 12% are due to cancers, representing approximately 0.4 million deceased individuals. Ethanol metabolism disturbs cell biochemistry by targeting the structure and function of essential biomolecules (proteins, nucleic acids, and lipids) and by provoking alterations in cell programming that lead to cancer development and cancer malignancy. A better understanding of the metabolic and cell signaling realm affected by ethanol is paramount to designing effective treatments and preventive actions tailored to specific neoplasias. Abstract The World Health Organization identifies alcohol as a cause of several neoplasias of the oropharynx cavity, esophagus, gastrointestinal tract, larynx, liver, or female breast. We review ethanol’s nonoxidative and oxidative metabolism and one-carbon metabolism that encompasses both redox and transfer reactions that influence crucial cell proliferation machinery. Ethanol favors the uncontrolled production and action of free radicals, which interfere with the maintenance of essential cellular functions. We focus on the generation of protein, DNA, and lipid adducts that interfere with the cellular processes related to growth and differentiation. Ethanol’s effects on stem cells, which are responsible for building and repairing tissues, are reviewed. Cancer stem cells (CSCs) of different origins suffer disturbances related to the expression of cell surface markers, enzymes, and transcription factors after ethanol exposure with the consequent dysregulation of mechanisms related to cancer metastasis or resistance to treatments. Our analysis aims to underline and discuss potential targets that show more sensitivity to ethanol’s action and identify specific metabolic routes and metabolic realms that may be corrected to recover metabolic homeostasis after pharmacological intervention. Specifically, research should pay attention to re-establishing metabolic fluxes by fine-tuning the functioning of specific pathways related to one-carbon metabolism and antioxidant processes.
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Affiliation(s)
- Francisco D. Rodriguez
- Department of Biochemistry and Molecular Biology, Faculty of Chemistry, University of Salamanca, 37007 Salamanca, Spain
- Group GIR USAL: BMD (Bases Moleculares del Desarrollo), 37007 Salamanca, Spain;
- Correspondence: ; Tel.: +34-677-510-030
| | - Rafael Coveñas
- Group GIR USAL: BMD (Bases Moleculares del Desarrollo), 37007 Salamanca, Spain;
- Institute of Neurosciences of Castilla y León (INCYL), Laboratory of Neuroanatomy of the Peptidergic Systems, University of Salamanca, 37007 Salamanca, Spain
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Seed LM. Horizon Scanning in Cancer Genomics: How Advances in Genomic Medicine Will Change Cancer Care Over the Next Decade. CURRENT GENETIC MEDICINE REPORTS 2021; 9:37-46. [PMID: 34306823 PMCID: PMC8280651 DOI: 10.1007/s40142-021-00200-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/27/2021] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW Advances in genomic medicine have the potential to revolutionise cancer patient care by driving forwards the clinical practice of precision oncology. This review aims to outline how genomic medicine advances may alter the care of cancer patients and their families over the next 10 years. RECENT FINDINGS The translation of oncogenomic advances into the clinical environment will likely be facilitated by the increasing availability of next-generation sequencing technologies and the increasing genomic literacy of healthcare professionals. The implementation of the centralised, nationwide NHS Genomic Medicine Service promises to improve equity of cancer care and to facilitate personalisation of almost every stage of the care pathway, from informing population screening and how we diagnose cancer to delivering prognoses and surveillance. Advances in cancer pharmacogenomics, and other "omics" technologies, have a tremendous potential to optimise patient care. Genomic medicine advances will also enhance the care offered to cancer patients' families. SUMMARY Genomic medicine advances are likely to transform almost every aspect of a cancer patient's care pathway. Cancer care will profoundly improve over the next decade, increasing UK cancer survival rates and improving patient outcomes.
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Affiliation(s)
- Lydia M. Seed
- School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0SP UK
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Targeted doxorubicin delivery and release within breast cancer environment using PEGylated chitosan nanoparticles labeled with monoclonal antibodies. Int J Biol Macromol 2021; 184:325-338. [PMID: 34119547 DOI: 10.1016/j.ijbiomac.2021.06.014] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 05/28/2021] [Accepted: 06/01/2021] [Indexed: 02/07/2023]
Abstract
Breast cancer has been one of the top chronic and life-threatening diseases worldwide. Nano-drug therapeutic systems have proved their efficacy as a selective treatment compared to the traditional ones that are associated with serious adverse effects. Here, biodegradable chitosan nanoparticles (CSNPs) were synthesized to provide selective and sustained release of doxorubicin (DOX) within the breast tumor microenvironment. CSNPs surface was modified using Polyethylene glycol (PEG) to enhance their blood circulation timing. To provide high drug selectivity, CSNPs functionalized with two different types of breast cancer-specific monoclonal antibodies (mAb); anti-human mammaglobin (Anti-hMAM) and anti-human epidermal growth factor (Anti-HER2). Anti-hMAM PEGylated DOX loaded CSNPs and Anti-HER2 PEGylated DOX loaded CSNPs nano-formulations were the most cytotoxic against MCF-7 cancer cells than L-929 normal cells compared to free DOX. Finally, we believe that dose-dependent system toxicity of freely ingested DOX can be managed with such targeted nano-formulated drug delivery platforms.
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Luo J, Yu J, Peng X. Could partial nonstarch polysaccharides ameliorate cancer by altering m 6A RNA methylation in hosts through intestinal microbiota? Crit Rev Food Sci Nutr 2021; 62:8319-8334. [PMID: 34036843 DOI: 10.1080/10408398.2021.1927975] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
There is a growing scientific view that the improvement of cancer by nonstarch polysaccharides (NSPs) is mediated by intestinal microbiota. Intestinal bacteria affect the supply of methyl donor substances and influence N6-methyladenosine (m6A) RNA methylation. As one of the epigenetic/epitranscriptomic modifications, m6A RNA methylation is closely related to the initiation and progression of cancers. This review summarizes the cancer-improving effects of NSPs through modulation of intestinal microbiota. It also summarizes the relationship between intestinal bacteria and the supply of methyl donor substances. Moreover, it also provides a summary of the effects of m6A RNA methylation on various types of cancer. The proposed mechanism is that, dietary consumed NSPs are utilized by specific intestinal bacteria and further reshape the microbial structure. Methyl donor substances will be directly or indirectly generated by the reshaped-microbiota, and affect the m6A RNA methylation of cancer-related and pro-carcinogenic inflammatory cytokine genes. Therefore, NSPs may change the m6A RNA methylation by affecting the methyl donor supply produced by intestinal microbiota and ameliorate cancer. This review discussed the possibility of cancer improvement of bioactive NSPs achieved by impacting RNA methylation via the intestinal microbiota, and it will offer new insights for the application of NSPs toward specific cancer prevention.
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Affiliation(s)
- Jianming Luo
- Department of Food Science and Engineering, Jinan University, Guangzhou, Guangdong, China
| | - Juntong Yu
- College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, China
| | - Xichun Peng
- Department of Food Science and Engineering, Jinan University, Guangzhou, Guangdong, China
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Momeni-Boroujeni A, Dahoud W, Vanderbilt CM, Chiang S, Murali R, Rios-Doria EV, Alektiar KM, Aghajanian C, Abu-Rustum NR, Ladanyi M, Ellenson LH, Weigelt B, Soslow RA. Clinicopathologic and Genomic Analysis of TP53-Mutated Endometrial Carcinomas. Clin Cancer Res 2021; 27:2613-2623. [PMID: 33602681 PMCID: PMC8530276 DOI: 10.1158/1078-0432.ccr-20-4436] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/16/2021] [Accepted: 02/11/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Copy number-high endometrial carcinomas were described by The Cancer Genome Atlas as high-grade endometrioid and serous cancers showing frequent copy-number alterations (CNA), low mutational burden (i.e., non-hypermutant), near-universal TP53 mutation, and unfavorable clinical outcomes. We sought to investigate and compare the clinicopathologic and molecular characteristics of non-hypermutant TP53-altered endometrial carcinomas of four histologic types. EXPERIMENTAL DESIGN TP53-mutated endometrial carcinomas, defined as TP53-mutant tumors lacking microsatellite instability or pathogenic POLE mutations, were identified (n = 238) in a cohort of 1,239 endometrial carcinomas subjected to clinical massively parallel sequencing of 410-468 cancer-related genes. Somatic mutations and CNAs (n = 238), and clinicopathologic features were determined (n = 185, initial treatment planning at our institution). RESULTS TP53-mutated endometrial carcinomas encompassed uterine serous (n = 102, 55.1%), high-grade endometrial carcinoma with ambiguous features/not otherwise specified (EC-NOS; n = 44, 23.8%), endometrioid carcinomas of all tumor grades (n = 28, 15.1%), and clear cell carcinomas (n = 11, 5.9%). PTEN mutations were significantly more frequent in endometrioid carcinomas, SPOP mutations in clear cell carcinomas, and CCNE1 amplification in serous carcinomas/EC-NOS; however, none of these genomic alterations were exclusive to any given histologic type. ERBB2 amplification was present at similar frequencies across TP53-mutated histologic types (7.7%-18.6%). Although overall survival was similar across histologic types, serous carcinomas presented more frequently at stage IV, had more persistent and/or recurrent disease, and reduced disease-free survival. CONCLUSIONS TP53-mutated endometrial carcinomas display clinical and molecular similarities across histologic subtypes. Our data provide evidence to suggest performance of ERBB2 assessment in all TP53-mutated endometrial carcinomas. Given the distinct clinical features of serous carcinomas, histologic classification continues to be relevant.
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Affiliation(s)
| | - Wissam Dahoud
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Chad M Vanderbilt
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Sarah Chiang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Rajmohan Murali
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Eric V Rios-Doria
- Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Kaled M Alektiar
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Carol Aghajanian
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nadeem R Abu-Rustum
- Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Marc Ladanyi
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Lora H Ellenson
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Britta Weigelt
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
| | - Robert A Soslow
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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