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Sun Z, Li Z, Wei Y, Xu L, Hang X, Kang Y. SMARCA4 Inhibits Breast Cancer Progression and Metastasis through RHOA Suppression. Cancer Res 2025; 85:1803-1818. [PMID: 39992701 PMCID: PMC12081196 DOI: 10.1158/0008-5472.can-24-2801] [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: 08/05/2024] [Revised: 01/07/2025] [Accepted: 02/19/2025] [Indexed: 02/26/2025]
Abstract
Triple-negative breast cancer (TNBC) is the most challenging subtype of the disease due to its aggressive nature and lack of targeted therapy options. To identify regulators of TNBC, we conducted a genome-wide CRISPR knockout screen in both three-dimensional (3D) tumor spheroid and two-dimensional cell culture models. The 3D spheroid model displayed unique potential in identifying putative tumor suppressors because of its closer mimicry of in vivo tumor growth conditions. Notably, the chromatin remodeling SWI/SNF complex emerged as a potent suppressor of tumor spheroid growth. Specifically, loss of the SWI/SNF ATPase subunit SMARCA4 promoted tumor spheroid growth with reduced compactness and enhanced primary tumor growth and metastasis across multiple TNBC models. SMARCA4 was required for the transcription of the Rho GTPase-activating factor ARHGAP29 by enhancing DNA accessibility through direct binding to its promoter. SMARCA4 loss resulted in reduced ARHGAP29 levels and hyperactive RHOA signaling, subsequently disrupting cell adhesion, facilitating the formation of a loose spheroid structure in vitro, and enhancing breast cancer growth and metastasis in vivo. These results establish SMARCA4 and SWI/SNF as tumor suppressors of TNBC through suppression of RHOA activity. Significance: CRISPR-knockout screen in 3D tumor spheroid revealed that SMARCA4, a SWI/SNF ATPase subunit, suppresses triple-negative breast cancer growth and metastasis by increasing ARHGAP29 transcription and inhibiting the RHOA signaling pathway.
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Affiliation(s)
- Zheng Sun
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544
| | - Zhuo Li
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544
- Present address: BeiGene Global Research, Shanghai, P.R. China
| | - Yong Wei
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544
- Ludwig Institute for Cancer Research, Princeton Branch, Princeton, NJ 08544
| | - Lillian Xu
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544
- Present address: Johns Hopkins University School of Medicine, Baltimore, MD, 21205
| | - Xiang Hang
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544
- Ludwig Institute for Cancer Research, Princeton Branch, Princeton, NJ 08544
| | - Yibin Kang
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544
- Ludwig Institute for Cancer Research, Princeton Branch, Princeton, NJ 08544
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Zamora I, Gutiérrez M, Pascual A, Pajares MJ, Barajas M, Perez LM, You S, Knudsen BS, Freeman MR, Encío IJ, Rotinen M. ONECUT2 is a druggable driver of luminal to basal breast cancer plasticity. Cell Oncol (Dordr) 2025; 48:83-99. [PMID: 38819630 PMCID: PMC11850477 DOI: 10.1007/s13402-024-00957-3] [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] [Accepted: 05/03/2024] [Indexed: 06/01/2024] Open
Abstract
PURPOSE Tumor heterogeneity complicates patient treatment and can be due to transitioning of cancer cells across phenotypic cell states. This process is associated with the acquisition of independence from an oncogenic driver, such as the estrogen receptor (ER) in breast cancer (BC), resulting in tumor progression, therapeutic failure and metastatic spread. The transcription factor ONECUT2 (OC2) has been shown to be a master regulator protein of metastatic castration-resistant prostate cancer (mCRPC) tumors that promotes lineage plasticity to a drug-resistant neuroendocrine (NEPC) phenotype. Here, we investigate the role of OC2 in the dynamic conversion between different molecular subtypes in BC. METHODS We analyze OC2 expression and clinical significance in BC using public databases and immunohistochemical staining. In vitro, we perform RNA-Seq, RT-qPCR and western-blot after OC2 enforced expression. We also assess cellular effects of OC2 silencing and inhibition with a drug-like small molecule in vitro and in vivo. RESULTS OC2 is highly expressed in a substantial subset of hormone receptor negative human BC tumors and tamoxifen-resistant models, and is associated with poor clinical outcome, lymph node metastasis and heightened clinical stage. OC2 inhibits ER expression and activity, suppresses a gene expression program associated with luminal differentiation and activates a basal-like state at the gene expression level. We also show that OC2 is required for cell growth and survival in metastatic BC models and that it can be targeted with a small molecule inhibitor providing a novel therapeutic strategy for patients with OC2 active tumors. CONCLUSIONS The transcription factor OC2 is a driver of BC heterogeneity and a potential drug target in distinct cell states within the breast tumors.
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Affiliation(s)
- Irene Zamora
- Department of Health Sciences, Public University of Navarre, Pamplona, Navarre, Spain
| | - Mirian Gutiérrez
- Department of Health Sciences, Public University of Navarre, Pamplona, Navarre, Spain
| | - Alex Pascual
- Department of Health Sciences, Public University of Navarre, Pamplona, Navarre, Spain
| | - María J Pajares
- Department of Health Sciences, Public University of Navarre, Pamplona, Navarre, Spain
- IdiSNA, Navarre Institute for Health Research, Pamplona, Navarre, Spain
| | - Miguel Barajas
- Department of Health Sciences, Public University of Navarre, Pamplona, Navarre, Spain
- IdiSNA, Navarre Institute for Health Research, Pamplona, Navarre, Spain
| | - Lillian M Perez
- Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Sungyong You
- Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | | | - Michael R Freeman
- Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Ignacio J Encío
- Department of Health Sciences, Public University of Navarre, Pamplona, Navarre, Spain
- IdiSNA, Navarre Institute for Health Research, Pamplona, Navarre, Spain
| | - Mirja Rotinen
- Department of Health Sciences, Public University of Navarre, Pamplona, Navarre, Spain.
- IdiSNA, Navarre Institute for Health Research, Pamplona, Navarre, Spain.
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Furuya K, Hirata H, Kobayashi T, Ishiguro H, Sokabe M. Volume-regulated anion channels conduct ATP in undifferentiated mammary cells and promote tumorigenesis in xenograft nude mouse. Front Cell Dev Biol 2025; 12:1519642. [PMID: 39882260 PMCID: PMC11774906 DOI: 10.3389/fcell.2024.1519642] [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: 10/30/2024] [Accepted: 12/26/2024] [Indexed: 01/31/2025] Open
Abstract
The high interstitial ATP concentration in the cancer microenvironment is a major source of adenosine, which acts as a strong immune suppressor. However, the source of ATP release has not been elucidated. We measured ATP release during hypotonic stress using a real-time ATP luminescence imaging system in breast cell lines and in primary cultured mammary cells. In breast cell lines, ATP was released with a slowly rising diffuse pattern, whereas in primary cultured cells, ATP was intermittently released with transient-sharp peaks. The diffuse ATP release pattern changed to a transient-sharp pattern by cholera toxin treatment and the reverse change was induced by transforming growth factor (TGF) β treatment. DCPIB, an inhibitor of volume-regulated anion channels (VRACs), suppressed the diffuse pattern. The inflammatory mediator sphingosine-1-phosphate (S1P) induced a diffuse ATP release pattern isovolumetrically. Knockdown of the A isoform of leucine-rich repeat-containing protein 8 (LRRC8A), the essential molecular entity of VRACs, using shRNA suppressed the diffuse pattern. In the nude mouse xenograft model, LRRC8A knockdown suppressed the tumorigenesis of subcutaneously implanted breast cancer cells. These results suggest that abundantly expressed VRACs are a conduit of ATP release in undifferentiated cells, including cancer cells.
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Affiliation(s)
- Kishio Furuya
- Department Human Nutrition, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Mechanobiology Laboratory, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroaki Hirata
- Mechanobiology Laboratory, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Human Information Systems Labs, Kanazawa Institute of Technology, Hakusan-shi, Ishikawa, Japan
| | - Takeshi Kobayashi
- Department Physiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroshi Ishiguro
- Department Human Nutrition, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masahiro Sokabe
- Mechanobiology Laboratory, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Human Information Systems Labs, Kanazawa Institute of Technology, Hakusan-shi, Ishikawa, Japan
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Cheng TC, Hung MC, Wang LH, Tu SH, Wu CH, Yen Y, Chen CL, Whang-Peng J, Lee WJ, Liao YC, Lee YC, Pan MH, Lin HK, Tzeng HE, Guo P, Chu CY, Chen LC, Ho YS. Histamine N-methyltransferase (HNMT) as a potential auxiliary biomarker for predicting adaptability to anti-HER2 drug treatment in breast cancer patients. Biomark Res 2025; 13:7. [PMID: 39789599 PMCID: PMC11720525 DOI: 10.1186/s40364-024-00715-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Accepted: 12/20/2024] [Indexed: 01/12/2025] Open
Abstract
BACKGROUND Up to 23% of breast cancer patients recurred within a decade after trastuzumab treatment. Conversely, one trial found that patients with low HER2 expression and metastatic breast cancer had a positive response to trastuzumab-deruxtecan (T-Dxd). This indicates that relying solely on HER2 as a single diagnostic marker to predict the efficacy of anti-HER2 drugs is insufficient. This study highlights the interaction between histamine N-methyltransferase (HNMT) and HER2 as an adjunct predictor for trastuzumab response. Furthermore, modulation of HER2 expression by HNMT may explain why those with low HER2 expression still respond to T-Dxd. METHODS We investigated the impact of HNMT protein expression on the efficacy of anti-HER2 therapy in both in vivo and ex vivo models of patient-derived xenografts and cell line-derived xenografts. Our analysis included Förster resonance energy transfer (FRET) to assess the interaction strength between HNMT and HER2 proteins in trastuzumab-resistant and sensitive tumor tissues. Additionally, we used fluorescence lifetime imaging microscopy (FLIM), cleaved luciferase, and immunoprecipitation to study the interaction dynamics of HNMT and HER2. Furthermore, we evaluated the influence of HNMT activity on the binding of anti-HER2 antibodies to their targets through flow cytometry. We also observed the nuclear translocation of HNMT/HER2-ICD cells using fluorescent double staining and DeltaVision microscopy. Finally, ChIP sequencing was employed to identify target genes affected by the HNMT/HER2-ICD complex. RESULTS This study highlights HNMT as a potential auxiliary biomarker for diagnosing HER2 + breast cancer. FRET analysis demonstrated a significant interaction between HNMT and HER2 protein in trastuzumab-sensitive tumor tissue (n = 50), suggesting the potential of HNMT as a predictor of treatment response. Mechanistic studies revealed that the interaction between HNMT and HER2 contributes to increased HER2 protein expression at the transcriptional level, thereby impacting the efficacy of anti-HER2 therapy. Furthermore, a subset of triple-negative breast cancers characterized by HNMT overexpression was found to be sensitive to HER2 antibody-drug conjugates such as T-Dxd. CONCLUSIONS These findings offer crucial insights for clinicians evaluating candidates for anti-HER2 therapy, especially for HER2-low breast cancer patients who could gain from T-Dxd treatment. Identifying HNMT expression could help clinicians pinpoint patients who would benefit from anti-HER2 therapy.
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Affiliation(s)
- Tzu-Chun Cheng
- Institute of Biochemistry and Molecular Biology, College of Life Sciences, China Medical University, Taichung, Taiwan
| | - Mien-Chie Hung
- Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Molecular Biology, Research Center for Cancer Biology, Cancer Biology and Precision Therapeutics Center, and Center for Molecular Medicine, China Medical University, Taichung, Taiwan
- Department of Biotechnology, Asia University, Taichung, Taiwan
| | - Lu-Hai Wang
- Institute of Integrated Medicine and Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
| | - Shih-Hsin Tu
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University; & Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan
| | - Chih-Hsiung Wu
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University; & Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan
| | - Yun Yen
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chi-Long Chen
- Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Pathology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
| | - Jacqueline Whang-Peng
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
| | - Wen-Jui Lee
- Institute of Biochemistry and Molecular Biology, College of Life Sciences, China Medical University, Taichung, Taiwan
| | - You-Cheng Liao
- Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Yu-Ching Lee
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
| | - Min-Hsiung Pan
- Institute of Food Sciences and Technology, National Taiwan University, Taipei, Taiwan
| | - Hui-Kuan Lin
- Department of Pathology, Duke University Medical Center, Duke University School of Medicine, Durham, NC, 27710, USA
| | - Huey-En Tzeng
- Division of Hematology/Medical Oncology, Department of Medicine, Taichung Veterans General Hospital, Taichung City, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung-Hsing University, Taichung, Taiwan
| | - Peixuan Guo
- Center for RNA Nanobiotechnology and Nanomedicine, College of Pharmacy, College of Medicine, Dorothy M. Davis Heart and Lung Research Institute, and James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA
| | - Cheng-Ying Chu
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
- CRISPR Gene Targeting Core, Taipei Medical University, Taipei, 110, Taiwan
| | - Li-Ching Chen
- Department of Biological Science & Technology, College of Life Sciences, China Medical University, Taichung, Taiwan.
| | - Yuan-Soon Ho
- Institute of Biochemistry and Molecular Biology, College of Life Sciences, China Medical University, Taichung, Taiwan.
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Fournier M, Javary J, Roh V, Fournier N, Radtke F. Reciprocal inhibition of NOTCH and SOX2 shapes tumor cell plasticity and therapeutic escape in triple-negative breast cancer. EMBO Mol Med 2024; 16:3184-3217. [PMID: 39478150 PMCID: PMC11628624 DOI: 10.1038/s44321-024-00161-8] [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: 05/07/2024] [Revised: 10/15/2024] [Accepted: 10/16/2024] [Indexed: 12/11/2024] Open
Abstract
Cancer cell plasticity contributes significantly to the failure of chemo- and targeted therapies in triple-negative breast cancer (TNBC). Molecular mechanisms of therapy-induced tumor cell plasticity and associated resistance are largely unknown. Using a genome-wide CRISPR-Cas9 screen, we investigated escape mechanisms of NOTCH-driven TNBC treated with a gamma-secretase inhibitor (GSI) and identified SOX2 as a target of resistance to Notch inhibition. We describe a novel reciprocal inhibitory feedback mechanism between Notch signaling and SOX2. Specifically, Notch signaling inhibits SOX2 expression through its target genes of the HEY family, and SOX2 inhibits Notch signaling through direct interaction with RBPJ. This mechanism shapes divergent cell states with NOTCH positive TNBC being more epithelial-like, while SOX2 expression correlates with epithelial-mesenchymal transition, induces cancer stem cell features and GSI resistance. To counteract monotherapy-induced tumor relapse, we assessed GSI-paclitaxel and dasatinib-paclitaxel combination treatments in NOTCH inhibitor-sensitive and -resistant TNBC xenotransplants, respectively. These distinct preventive combinations and second-line treatment option dependent on NOTCH1 and SOX2 expression in TNBC are able to induce tumor growth control and reduce metastatic burden.
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Affiliation(s)
- Morgane Fournier
- Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, Swiss Institute for Experimental Cancer Research (ISREC), Swiss Cancer Center Leman (SCCL), Station 19, CH-1015, Lausanne, Switzerland
| | - Joaquim Javary
- Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, Swiss Institute for Experimental Cancer Research (ISREC), Swiss Cancer Center Leman (SCCL), Station 19, CH-1015, Lausanne, Switzerland
| | - Vincent Roh
- Translational Data Science Facility, Swiss Institute of Bioinformatics (SIB), AGORA Cancer Research Center, CH-1011, Lausanne, Switzerland
| | - Nadine Fournier
- Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, Swiss Institute for Experimental Cancer Research (ISREC), Swiss Cancer Center Leman (SCCL), Station 19, CH-1015, Lausanne, Switzerland
- Translational Data Science Facility, Swiss Institute of Bioinformatics (SIB), AGORA Cancer Research Center, CH-1011, Lausanne, Switzerland
| | - Freddy Radtke
- Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, Swiss Institute for Experimental Cancer Research (ISREC), Swiss Cancer Center Leman (SCCL), Station 19, CH-1015, Lausanne, Switzerland.
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6
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Zheng W, Marini W, Murakami K, Sotov V, Butler M, Gorrini C, Ohashi PS, Reedijk M. Caspase-1-dependent spatiality in triple-negative breast cancer and response to immunotherapy. Nat Commun 2024; 15:8514. [PMID: 39353903 PMCID: PMC11445480 DOI: 10.1038/s41467-024-52553-6] [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: 03/14/2024] [Accepted: 09/12/2024] [Indexed: 10/03/2024] Open
Abstract
Tumor immune microenvironment (TIME) spatial organization predicts outcome and therapy response in triple-negative breast cancer (TNBC). An immunosuppressive TIME containing elevated tumor-associated macrophages (TAM) and scarce CD8+ T cells is associated with poor outcome, but the regulatory mechanisms are poorly understood. Here we show that ETS1-driven caspase-1 expression, required for IL1β processing and TAM recruitment, is negatively regulated by estrogen receptors alpha (ERα) and a defining feature of TNBC. Elevated tumoral caspase-1 is associated with a distinct TIME characterized by increased pro-tumoral TAMs and CD8+ T cell exclusion from tumor nests. Mouse models prove the functional importance of ERα, ETS1, caspase-1 and IL1β in TIME conformation. Caspase-1 inhibition induces an immunoreactive TIME and reverses resistance to immune checkpoint blockade, identifying a therapeutically targetable mechanism that governs TNBC spatial organization.
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Affiliation(s)
- Weiyue Zheng
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Wanda Marini
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Kiichi Murakami
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Valentin Sotov
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Marcus Butler
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, ON, Canada
| | - Chiara Gorrini
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- School of Molecular and Cellular Biology, University of Leeds, Leeds, UK
| | - Pamela S Ohashi
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Department of Immunology, University of Toronto, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Michael Reedijk
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
- Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
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Das P, San Martin R, Hong T, McCord RP. Rearrangement of 3D genome organization in breast cancer epithelial - mesenchymal transition and metastasis organotropism. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.23.609227. [PMID: 39229150 PMCID: PMC11370564 DOI: 10.1101/2024.08.23.609227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
Breast cancer cells exhibit organotropism during metastasis, showing preferential homing to certain organs such as bone, lung, liver, and brain. One potential explanation for this organotropic behavior is that cancer cells gain properties that enable thriving in certain microenvironments. Such specific metastatic traits may arise from gene regulation at the primary tumor site. Spatial genome organization plays a crucial role in oncogenic transformation and progression, but the extent to which chromosome architecture contributes to organ-specific metastatic traits is unclear. This work characterizes chromosome architecture changes associated with organotropic metastatic traits. By comparing a collection of genomic data from different subtypes of localized and lung metastatic breast cancer cells with both normal and cancerous lung cells, we find important trends of genomic reorganization. The most striking differences in 3D genome compartments segregate cell types according to their epithelial vs. mesenchymal status. This EMT compartment signature occurs at genomic regions distinct from transcription-defined EMT signatures, suggesting a separate layer of regulation. Specifically querying organotropism, we find 3D genome changes consistent with adaptations needed to survive in a new microenvironment, with lung metastatic breast cells exhibiting compartment switch signatures that shift the genome architecture to a lung cell-like conformation and brain metastatic prostate cancer cells showing compartment shifts toward a brain-like state. TCGA patient data reveals gene expression changes concordant with these organ-permissive compartment changes. These results suggest that genome architecture provides an additional level of cell fate specification informing organotropism and enabling survival at the metastatic site.
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Subramani R, Chatterjee A, Pedroza DA, Poudel S, Rajkumar P, Annabi J, Penner E, Lakshmanaswamy R. 2-methoxyestradiol inhibits the malignant behavior of triple negative breast cancer cells by altering their miRNome. Front Oncol 2024; 14:1371792. [PMID: 39328201 PMCID: PMC11424607 DOI: 10.3389/fonc.2024.1371792] [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: 01/17/2024] [Accepted: 08/19/2024] [Indexed: 09/28/2024] Open
Abstract
Background Triple-negative breast cancer (TNBC) is a subtype of breast cancer with no effective targeted treatment currently available. Estrogen and its metabolites influence the growth of mammary cancer. Previously, we demonstrated the anti-cancer effects of 2-methoxyestradiol (2ME2) on mammary carcinogenesis. Materials and methods In the present study, we investigated the effects of 2ME2 on TNBC cells. TNBC (MDA-MB-231 and MDA-MB-468) and non-tumorigenic breast (MCF10A) cell lines were used to determine the effects of 2ME2 on cell proliferation (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium; MTS assay), cell cycle (flow cytometric assay), migration (transwell migration assay), invasion (matrigel invasion assay), apoptosis (annexin V/propidium iodide assay), colony formation (soft agar assay), and miRNome (human miRNA profiling array). The miRNome data were analyzed using the c-BioPortal and Xena platforms. Moreover, Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and reactome pathway analyses were performed. Results We found that 2ME2 effectively inhibited cell proliferation and induced apoptosis. Furthermore, 2ME2 treatment arrested TNBC cells in the S-phase of the cell cycle. Treatment with 2ME2 also significantly decreased the aggressiveness of TNBC cells by inhibiting their migration and invasion. In addition, 2ME2 altered the miRNA expression in these cells. In silico analysis of the miRNome profile of 2ME2-treated MDA-MB-468 cells revealed that miRNAs altered the target genes involved in many different cancer hallmarks. Conclusion 2ME2 inhibits triple negative breast cancer by impacting major cellular processes like proliferation, apoptosis, metastasis, etc. It further modifies gene expression by altering the miRNome of triple negative breast cancer cells. Overall, our findings suggest 2ME2 as a potent anti-cancer drug for the treatment of TNBC.
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Affiliation(s)
- Ramadevi Subramani
- Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, TX, United States
- Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, United States
| | - Animesh Chatterjee
- Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, TX, United States
| | - Diego A Pedroza
- Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, United States
| | - Seeta Poudel
- Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, TX, United States
| | - Preetha Rajkumar
- College of Osteopathic Medicine, Rocky Vista University, Ivins, UT, United States
| | - Jeffrey Annabi
- Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, TX, United States
| | - Elizabeth Penner
- Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, TX, United States
| | - Rajkumar Lakshmanaswamy
- Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, TX, United States
- Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, United States
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Jamroze A, Liu X, Tang DG. Treatment-induced stemness and lineage plasticity in driving prostate cancer therapy resistance. CANCER HETEROGENEITY AND PLASTICITY 2024; 1:0005. [PMID: 39363904 PMCID: PMC11449474 DOI: 10.47248/chp2401010005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/05/2024]
Abstract
Most human cancers are heterogeneous consisting of cancer cells at different epigenetic and transcriptional states and with distinct phenotypes, functions, and drug sensitivities. This inherent cancer cell heterogeneity contributes to tumor resistance to clinical treatment, especially the molecularly targeted therapies such as tyrosine kinase inhibitors (TKIs) and androgen receptor signaling inhibitors (ARSIs). Therapeutic interventions, in turn, induce lineage plasticity (also called lineage infidelity) in cancer cells that also drives therapy resistance. In this Perspective, we focus our discussions on cancer cell lineage plasticity manifested as treatment-induced switching of epithelial cancer cells to basal/stem-like, mesenchymal, and neural lineages. We employ prostate cancer (PCa) as the prime example to highlight ARSI-induced lineage plasticity during and towards development of castration-resistant PCa (CRPC). We further discuss how the tumor microenvironment (TME) influences therapy-induced lineage plasticity. Finally, we offer an updated summary on the regulators and mechanisms driving cancer cell lineage infidelity, which should be therapeutically targeted to extend the therapeutic window and improve patients' survival.
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Affiliation(s)
- Anmbreen Jamroze
- Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Xiaozhuo Liu
- Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Dean G. Tang
- Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Experimental Therapeutics (ET) Graduate Program, University at Buffalo & Roswell Park Comprehensive Cancer Center, NY 14263, USA
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10
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Chen WJ, Ye QQ, Wu HT, Wu Z, Lan YZ, Fang ZX, Lin WT, Liu J. MiR-338-5p, a novel metastasis-related miRNA, inhibits triple-negative breast cancer progression by targeting the ETS1/NOTCH1 axis. Heliyon 2024; 10:e34949. [PMID: 39157351 PMCID: PMC11327603 DOI: 10.1016/j.heliyon.2024.e34949] [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: 07/11/2024] [Accepted: 07/18/2024] [Indexed: 08/20/2024] Open
Abstract
Breast cancer ranks as the most prevalent cancer globally, surpassing lung cancer, with recurrence/metastasis to be its main account for the cancer-related mortality. MicroRNAs (miRNAs) participate critically in various physiological and pathological processes through posttranscriptional regulation of downstream genes. Our preliminary findings identified miR-338-5p, potentially linked to metastasis in breast cancer, a previously unexplored area. Analysis of the GSE38867 dataset revealed the decreased miR-338-5p expression in metastatic breast cancer compared to normal tissues. Cellular function experiments and a xenograft tumor model demonstrated the inhibitory function of miR-338-5p on the progression of breast cancer in vitro and in vivo. Furthermore, it downregulated the expression of mesenchymal biomarkers and NOTCH1 significantly. With the predicting targets of miR-338-5p and transcription factors of the NOTCH1 gene, coupled with dual luciferase reporter assays, it is identified ETS1 as the interactor between miR-338-5p and NOTCH1. In breast cancer tissues, as well as in our xenograft tumor model, expression of ETS1 and NOTCH1 was positively correlated using immunohistochemical staining. This study reports, for the first time, on the miR-338-5p/ETS1/NOTCH1 axis and its pivotal role in breast cancer proliferation and metastasis. These findings propose a novel therapeutic strategy for breast cancer patients and lays a foundation for its clinical detection and treatment evaluation.
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Affiliation(s)
- Wen-Jia Chen
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, 515041, China
- Department of Physiology, Shantou University Medical College, Shantou, 515041, China
| | - Qian-Qian Ye
- Department of Pathology, Ganzhou Women and Children's Health Care Hospital, Ganzhou, 341000, China
| | - Hua-Tao Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
| | - Zheng Wu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, 515041, China
- Department of Physiology, Shantou University Medical College, Shantou, 515041, China
| | - Yang-Zheng Lan
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, 515041, China
- Department of Physiology, Shantou University Medical College, Shantou, 515041, China
| | - Ze-Xuan Fang
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, 515041, China
- Department of Physiology, Shantou University Medical College, Shantou, 515041, China
| | - Wen-Ting Lin
- Department of Pathology, Shantou University Medical College, Shantou, 515041, China
| | - Jing Liu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, 515041, China
- Department of Physiology, Shantou University Medical College, Shantou, 515041, China
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11
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Razavi-Mohseni M, Huang W, Guo YA, Shigaki D, Ho SWT, Tan P, Skanderup AJ, Beer MA. Machine learning identifies activation of RUNX/AP-1 as drivers of mesenchymal and fibrotic regulatory programs in gastric cancer. Genome Res 2024; 34:680-695. [PMID: 38777607 PMCID: PMC11216402 DOI: 10.1101/gr.278565.123] [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: 09/26/2023] [Accepted: 05/13/2024] [Indexed: 05/25/2024]
Abstract
Gastric cancer (GC) is the fifth most common cancer worldwide and is a heterogeneous disease. Among GC subtypes, the mesenchymal phenotype (Mes-like) is more invasive than the epithelial phenotype (Epi-like). Although gene expression of the epithelial-to-mesenchymal transition (EMT) has been studied, the regulatory landscape shaping this process is not fully understood. Here we use ATAC-seq and RNA-seq data from a compendium of GC cell lines and primary tumors to detect drivers of regulatory state changes and their transcriptional responses. Using the ATAC-seq data, we developed a machine learning approach to determine the transcription factors (TFs) regulating the subtypes of GC. We identified TFs driving the mesenchymal (RUNX2, ZEB1, SNAI2, AP-1 dimer) and the epithelial (GATA4, GATA6, KLF5, HNF4A, FOXA2, GRHL2) states in GC. We identified DNA copy number alterations associated with dysregulation of these TFs, specifically deletion of GATA4 and amplification of MAPK9 Comparisons with bulk and single-cell RNA-seq data sets identified activation toward fibroblast-like epigenomic and expression signatures in Mes-like GC. The activation of this mesenchymal fibrotic program is associated with differentially accessible DNA cis-regulatory elements flanking upregulated mesenchymal genes. These findings establish a map of TF activity in GC and highlight the role of copy number driven alterations in shaping epigenomic regulatory programs as potential drivers of GC heterogeneity and progression.
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Affiliation(s)
- Milad Razavi-Mohseni
- Department of Biomedical Engineering and McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA
| | - Weitai Huang
- Laboratory of Computational Cancer Genomics, Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore 138672
| | - Yu A Guo
- Laboratory of Computational Cancer Genomics, Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore 138672
| | - Dustin Shigaki
- Department of Biomedical Engineering and McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA
| | - Shamaine Wei Ting Ho
- Laboratory of Cancer Epigenetic Regulation, Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore 138672
| | - Patrick Tan
- Laboratory of Cancer Epigenetic Regulation, Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore 138672
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore 169857
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593
| | - Anders J Skanderup
- Laboratory of Computational Cancer Genomics, Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore 138672
| | - Michael A Beer
- Department of Biomedical Engineering and McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA;
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12
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Mares-Quiñones MD, Galán-Vásquez E, Pérez-Rueda E, Pérez-Ishiwara DG, Medel-Flores MO, Gómez-García MDC. Identification of modules and key genes associated with breast cancer subtypes through network analysis. Sci Rep 2024; 14:12350. [PMID: 38811600 PMCID: PMC11137066 DOI: 10.1038/s41598-024-61908-4] [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: 07/13/2023] [Accepted: 05/10/2024] [Indexed: 05/31/2024] Open
Abstract
Breast cancer is the most common malignancy in women around the world. Intratumor and intertumoral heterogeneity persist in mammary tumors. Therefore, the identification of biomarkers is essential for the treatment of this malignancy. This study analyzed 28,143 genes expressed in 49 breast cancer cell lines using a Weighted Gene Co-expression Network Analysis to determine specific target proteins for Basal A, Basal B, Luminal A, Luminal B, and HER2 ampl breast cancer subtypes. Sixty-five modules were identified, of which five were characterized as having a high correlation with breast cancer subtypes. Genes overexpressed in the tumor were found to participate in the following mechanisms: regulation of the apoptotic process, transcriptional regulation, angiogenesis, signaling, and cellular survival. In particular, we identified the following genes, considered as hubs: IFIT3, an inhibitor of viral and cellular processes; ETS1, a transcription factor involved in cell death and tumorigenesis; ENSG00000259723 lncRNA, expressed in cancers; AL033519.3, a hypothetical gene; and TMEM86A, important for regulating keratinocyte membrane properties, considered as a key in Basal A, Basal B, Luminal A, Luminal B, and HER2 ampl breast cancer subtypes, respectively. The modules and genes identified in this work can be used to identify possible biomarkers or therapeutic targets in different breast cancer subtypes.
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Affiliation(s)
- María Daniela Mares-Quiñones
- Laboratorio de Biomedicina Molecular, Programa de Doctorado en Biotecnología, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Ciudad de México, Mexico
| | - Edgardo Galán-Vásquez
- Departamento de Ingeniería de Sistemas Computacionales y Automatización, Instituto de Investigaciones en Matemáticas Aplicadas y en Sistemas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Ciudad de México, Mexico
| | - Ernesto Pérez-Rueda
- Instituto de Investigaciones en Matemáticas Aplicadas y en Sistemas, Universidad Nacional Autónoma de México, Unidad Académica del Estado de Yucatán, Mérida, Mexico
| | - D Guillermo Pérez-Ishiwara
- Laboratorio de Biomedicina Molecular, Programa de Doctorado en Biotecnología, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Ciudad de México, Mexico
| | - María Olivia Medel-Flores
- Laboratorio de Biomedicina Molecular, Programa de Doctorado en Biotecnología, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Ciudad de México, Mexico
| | - María Del Consuelo Gómez-García
- Laboratorio de Biomedicina Molecular, Programa de Doctorado en Biotecnología, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Ciudad de México, Mexico.
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13
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Salim EI, Alabasy MM, Nashar EME, Al-Zahrani NS, Alzahrani MA, Guo Z, Beltagy DM, Shahen M. Molecular interactions between metformin and D-limonene inhibit proliferation and promote apoptosis in breast and liver cancer cells. BMC Complement Med Ther 2024; 24:185. [PMID: 38711049 PMCID: PMC11071183 DOI: 10.1186/s12906-024-04453-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 03/22/2024] [Indexed: 05/08/2024] Open
Abstract
BACKGROUND Cancer is a fatal disease that severely affects humans. Designing new anticancer strategies and understanding the mechanism of action of anticancer agents is imperative. HYPOTHESIS/PURPOSE In this study, we evaluated the utility of metformin and D-limonene, alone or in combination, as potential anticancer therapeutics using the human liver and breast cancer cell lines HepG2 and MCF-7. STUDY DESIGN An integrated systems pharmacology approach is presented for illustrating the molecular interactions between metformin and D-limonene. METHODS We applied a systems-based analysis to introduce a drug-target-pathway network that clarifies different mechanisms of treatment. The combination treatment of metformin and D-limonene induced apoptosis in both cell lines compared with single drug treatments, as indicated by flow cytometric and gene expression analysis. RESULTS The mRNA expression of Bax and P53 genes were significantly upregulated while Bcl-2, iNOS, and Cox-2 were significantly downregulated in all treatment groups compared with normal cells. The percentages of late apoptotic HepG2 and MCF-7 cells were higher in all treatment groups, particularly in the combination treatment group. Calculations for the combination index (CI) revealed a synergistic effect between both drugs for HepG2 cells (CI = 0.14) and MCF-7 cells (CI = 0.22). CONCLUSION Our data show that metformin, D-limonene, and their combinations exerted significant antitumor effects on the cancer cell lines by inducing apoptosis and modulating the expression of apoptotic genes.
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Affiliation(s)
- Elsayed I Salim
- Department of Zoology, Research Lab of Molecular Carcinogenesis, Faculty of Science, Tanta University, Tanta, 31527, Egypt.
| | - Mona M Alabasy
- Department of Zoology, Research Lab of Molecular Carcinogenesis, Faculty of Science, Tanta University, Tanta, 31527, Egypt
| | - Eman M El Nashar
- Department of Anatomy, College of Medicine, King Khalid University, Abha, 62529, Saudi Arabia
| | - Norah S Al-Zahrani
- Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha, 62529, Saudi Arabia
| | - Mohammed A Alzahrani
- Internal Medicine Department, College of Medicine, King Khalid University, Abha, 62529, Saudi Arabia
| | - Zihu Guo
- College of Life Science, Center of Bioinformatics, Northwest A and F University, Yangling, Shaanxi, 712100, China
| | - Doha M Beltagy
- Biochemistry Department, Faculty of Science, Damanhour University, Damanhour, Egypt
| | - Mohamed Shahen
- Department of Zoology, Research Lab of Molecular Carcinogenesis, Faculty of Science, Tanta University, Tanta, 31527, Egypt.
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14
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Sahraoui G, Rahoui N, Driss M, Mrad K. Inflammatory breast cancer: An overview about the histo-pathological aspect and diagnosis. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 384:47-61. [PMID: 38637099 DOI: 10.1016/bs.ircmb.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/20/2024]
Abstract
Inflammatory Breast Cancer (IBC) is a rare and aggressive form of locally advanced breast cancer, classified as stage T4d according to the tumor-node-metastasis staging criteria. This subtype of breast cancer is known for its rapid progression and significantly lower survival rates compared to other forms of breast cancer. Despite its distinctive clinical features outlined by the World Health Organization, the histopathological characteristics of IBC remain not fully elucidated, presenting challenges in its diagnosis and treatment. Histologically, IBC tumors often exhibit a ductal phenotype, characterized by emboli composed of pleomorphic cells with a high nuclear grade. These emboli are predominantly found in the papillary and reticular dermis of the skin overlaying the breast, suggesting a primary involvement of the lymphatic vessels. The tumor microenvironment in IBC is a complex network involving various cells such as macrophages, monocytes, and predominantly T CD8+ lymphocytes, and elements including blood vessels and extracellular matrix molecules, which play a pivotal role in the aggressive nature of IBC. A significant aspect of IBC is the frequent loss of expression of hormone receptors like estrogen and progesterone receptors, a phenomenon that is still under active investigation. Moreover, the overexpression of ERBB2/HER2 and TP53 in IBC cases is a topic of ongoing debate, with studies indicating a higher prevalence in IBC compared to non-inflammatory breast cancer. This overview seeks to provide a comprehensive understanding of the histopathological features and diagnostic approaches to IBC, emphasizing the critical areas that require further research.
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Affiliation(s)
- Ghada Sahraoui
- Department of histopathology, Salah Azaiez Cancer Institute, Tunisia.
| | - Nabil Rahoui
- Department of Pathology and Laboratory Medicine, University of North Carolina Chapel Hill, United States
| | - Maha Driss
- Department of histopathology, Salah Azaiez Cancer Institute, Tunisia
| | - Karima Mrad
- Department of histopathology, Salah Azaiez Cancer Institute, Tunisia
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15
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Yadollahi Farsani M, Amini Farsani Z, Teimuri S, Kolahdouzan M, Eshraghi Samani R, Teimori H. Deregulation of miR-1245b-5p and miR-92a-3p and their potential target gene, GATA3, in epithelial-mesenchymal transition pathway in breast cancer. Cancer Rep (Hoboken) 2024; 7:e1955. [PMID: 38173189 PMCID: PMC10849934 DOI: 10.1002/cnr2.1955] [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: 08/01/2022] [Revised: 11/30/2023] [Accepted: 12/04/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) are small molecules that have prominent roles in tumor development and metastasis and can be used for diagnostic and therapeutic purposes. This study evaluated the expression of miR-92a-3p and miR-1245b-5p and their potential target gene, GATA3 in patients with breast cancer (BC). MATERIALS AND METHODS In the search for BC-related microRNAs, miR-124b-5p and miR-92a-3p were selected using Medline through PubMed, miR2disease, miRcancer and miRTarBase. Moreover, target gene GATA3 and their possible interaction in the regulating epithelial-mesenchymal transition (EMT) and invasion was evaluated using in silico tools including miRTarBase, TargetScan, STRING-db, and Cytoscape. The expression level of miR-92a-3p, miR1245b-5p, and GATA3 were assessed on extracted RNAs of tumor and nontumor tissues from 36 patients with BC using qPCR. Additionally, clinical-pathologic characteristics, such as tumor grade, tumor stage, lymph node were taken into consideration and the diagnostic power of these miRNAs and GATA3 was evaluated using the ROC curve analysis. RESULTS In silico evaluation of miR-92a-3p and miR-1245b-5p supports their potential association with EMT and invasion signaling pathways in BC pathogenesis. Comparing tumor tissues to nontumor tissues, we found a significant downregulation of miR-1245b-5p and miR-92a-3p and upregulation of GATA3. Patients with BC who had decreased miR-92a-3p expression also had higher rates of advanced stage/grade and ER expression, whereas decreased miR-1245b-5p expression was only linked to ER expression and was not associated with lymph node metastasis. The AUC of miR-1245b-5p, miR-92a-3p, and GATA3 using ROC curve was determined 0.6449 (p = .0239), 0.5980 (p = .1526), and 0.7415 (p < .0001), respectively, which showed a significant diagnostic accuracy of miR-1245b-5p and GATA3 between the BC patients and healthy individuals. CONCLUSION MiR-1245b-5p, miR-92a-3p, and GATA3 gene contribute to BC pathogenesis and they may be having potential regulatory roles in signaling pathways involved in invasion and EMT pathways in BC pathogenesis, as a result of these findings. More research is needed to determine the regulatory mechanisms that they control.
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Affiliation(s)
- Mahtab Yadollahi Farsani
- Department of Medical Biotechnology, School of Advanced TechnologiesShahrekord University of Medical SciencesShahrekordIran
| | - Zeinab Amini Farsani
- Cellular and Molecular Research Center, Basic Health Sciences InstituteShahrekord University of Medical SciencesShahrekordIran
| | | | - Mohsen Kolahdouzan
- Department of Surgery, School of MedicineIsfahan University of Medical SciencesIsfahanIran
| | - Reza Eshraghi Samani
- Department of Surgery, School of MedicineIsfahan University of Medical SciencesIsfahanIran
| | - Hossein Teimori
- Cellular and Molecular Research Center, Basic Health Sciences InstituteShahrekord University of Medical SciencesShahrekordIran
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16
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Silva D, Quintas C, Gonçalves J, Fresco P. β 2-Adrenoceptor Activation Favor Acquisition of Tumorigenic Properties in Non-Tumorigenic MCF-10A Breast Epithelial Cells. Cells 2024; 13:262. [PMID: 38334654 PMCID: PMC10854540 DOI: 10.3390/cells13030262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 01/22/2024] [Accepted: 01/26/2024] [Indexed: 02/10/2024] Open
Abstract
Noradrenaline and adrenaline, and their cognate receptors, are currently accepted to participate in cancer progression. They may also participate in cancer initiation, although their role in this phase is much less explored. The aim of this work was to study the influence of adrenergic stimulation in several processes related to breast cancer carcinogenesis, using several adrenergic agonists in the MCF-10A non-tumorigenic breast cells. Activation of the β-adrenoceptors promoted an epithelial phenotype in MCF-10A cells, revealed by an increased expression of the epithelial marker E-cadherin and a decrease in the mesenchymal markers, N-cadherin and vimentin. MCF-10A cell motility and migration were also impaired after the β-adrenoceptors activation. Concomitant with this effect, β-adrenoceptors decrease cell protrusions (lamellipodia and filopodia) while increasing cell adhesion. Activation of the β-adrenoceptors also decreases MCF-10A cell proliferation. When the MCF-10A cells were cultured under low attachment conditions, activation the of β- (likely β2) or of α2-adrenoceptors had protective effects against cell death, suggesting a pro-survival role of these adrenoceptors. Overall, our results showed that, in breast cells, adrenoceptor activation (mainly through β-adrenoceptors) may be a risk factor in breast cancer by inducing some cancer hallmarks, providing a mechanistic explanation for the increase in breast cancer incidences that may be associated with conditions that cause massive adrenergic stimulation, such as stress.
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Affiliation(s)
- Dany Silva
- Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; (D.S.); (C.Q.); (P.F.)
- UCIBIO—Applied Molecular Biosciences Unit, Associate Laboratory i4HB, Institute for Health and Bioeconomy, University of Porto, 4050-313 Porto, Portugal
| | - Clara Quintas
- Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; (D.S.); (C.Q.); (P.F.)
- UCIBIO—Applied Molecular Biosciences Unit, Associate Laboratory i4HB, Institute for Health and Bioeconomy, University of Porto, 4050-313 Porto, Portugal
| | - Jorge Gonçalves
- Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; (D.S.); (C.Q.); (P.F.)
- UCIBIO—Applied Molecular Biosciences Unit, Associate Laboratory i4HB, Institute for Health and Bioeconomy, University of Porto, 4050-313 Porto, Portugal
| | - Paula Fresco
- Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; (D.S.); (C.Q.); (P.F.)
- UCIBIO—Applied Molecular Biosciences Unit, Associate Laboratory i4HB, Institute for Health and Bioeconomy, University of Porto, 4050-313 Porto, Portugal
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17
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Saitoh M. Transcriptional regulation of EMT transcription factors in cancer. Semin Cancer Biol 2023; 97:21-29. [PMID: 37802266 DOI: 10.1016/j.semcancer.2023.10.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 12/01/2022] [Accepted: 10/02/2023] [Indexed: 10/08/2023]
Abstract
The epithelial-mesenchymal transition (EMT) is one of the processes by which epithelial cells transdifferentiate into mesenchymal cells in the developmental stage, known as "complete EMT." In epithelial cancer, EMT, also termed "partial EMT," is associated with invasion, metastasis, and resistance to therapy, and is elicited by several transcription factors, frequently referred to as EMT transcription factors. Among these transcription factors that regulate EMT, ZEB1/2 (ZEB1 and ZEB2), SNAIL, and TWIST play a prominent role in driving the EMT process (hereafter referred to as "EMT-TFs"). Among these, ZEB1/2 show positive correlation with both expression of mesenchymal marker proteins and the aggressiveness of various carcinomas. On the other hand, TWIST and SNAIL are also correlated with the aggressiveness of carcinomas, but are not highly correlated with mesenchymal marker protein expression. Interestingly, these EMT-TFs are not detected simultaneously in any studied cases of aggressive cancers, except for sarcoma. Thus, only one or some of the EMT-TFs are expressed at high levels in cells of aggressive carcinomas. Expression of EMT-TFs is regulated by transforming growth factor-β (TGF-β), a well-established inducer of EMT, in cooperation with other signaling molecules, such as active RAS signals. The focus of this review is the molecular mechanisms by which EMT-TFs are transcriptionally sustained at sufficiently high levels in cells of aggressive carcinomas and upregulated by TGF-β during cancer progression.
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Affiliation(s)
- Masao Saitoh
- Center for Medical Education and Sciences, Graduate School of Medicine, University of Yamanashi, Chuo-city, Yamanashi, Japan.
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18
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Xiang S, Zhang W, Liu S, Hoadley KA, Perou CM, Zhang K, Marron JS. PAIRWISE NONLINEAR DEPENDENCE ANALYSIS OF GENOMIC DATA. Ann Appl Stat 2023; 17:2924-2943. [PMID: 38046186 PMCID: PMC10688600 DOI: 10.1214/23-aoas1745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2023]
Abstract
In The Cancer Genome Atlas (TCGA) data set, there are many interesting nonlinear dependencies between pairs of genes that reveal important relationships and subtypes of cancer. Such genomic data analysis requires a rapid, powerful and interpretable detection process, especially in a high-dimensional environment. We study the nonlinear patterns among the expression of pairs of genes from TCGA using a powerful tool called Binary Expansion Testing. We find many nonlinear patterns, some of which are driven by known cancer subtypes, some of which are novel.
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Affiliation(s)
- Siqi Xiang
- Department of Statistics and Operations Research, University of North Carolina at Chapel Hill
| | - Wan Zhang
- Department of Statistics and Operations Research, University of North Carolina at Chapel Hill
| | - Siyao Liu
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
- Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill
- Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill
| | - Katherine A. Hoadley
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
- Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill
- Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill
| | - Charles M. Perou
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
- Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill
- Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill
| | - Kai Zhang
- Department of Statistics and Operations Research, University of North Carolina at Chapel Hill
| | - J. S. Marron
- Department of Statistics and Operations Research, University of North Carolina at Chapel Hill
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
- Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill
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19
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Uematsu H, Saito C, Kondo J, Onuma K, Coppo R, Mori Y, Muto M, Kikawa Y, Tada M, Sugie T, Inoue M. De-differentiation in cultures of organoids from luminal-type breast cancer is restored by inhibition of NOTCH signaling. Hum Cell 2023; 36:2099-2112. [PMID: 37634223 DOI: 10.1007/s13577-023-00975-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 08/20/2023] [Indexed: 08/29/2023]
Abstract
Estrogen receptor (ER) expression in breast cancer can change during progression and the treatment, but the mechanism has not been well studied. In this study, we successfully prepared organoids from samples obtained from 33 luminal-type breast cancer patients and studied their ER expression. The expression status was well maintained in primary organoids, whereas it decreased after passaging in most of the cases. In fact, the studied organoid lines were classified into those that retained a high level of ER expression (9%), those that completely lost it (9%), and those that repressed it to varying degrees (82%). In some cases, the ER expression was suddenly and drastically decreased after passaging. Marker protein immunohistochemistry revealed that after passaging, the differentiation status shifted from a luminal- to a basal-like status. Differentially expressed genes suggested the activation of NOTCH signaling in the passaged organoids, wherein a NOTCH inhibitor was able to substantially rescue the decreased ER expression and alter the differentiation status. Our findings suggest that the differentiation status of luminal-type cancer cells is quite flexible, and that by inhibiting the NOTCH signaling we can preserve the differentiation status of luminal-type breast cancer organoids.
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Affiliation(s)
- Hiroyuki Uematsu
- Department of Clinical Bio-Resource Research and Development, Graduate School of Medicine, Kyoto University, 46-29, Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8304, Japan
- KBBM Inc, 46-29, Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8304, Japan
| | - Chieko Saito
- Department of Clinical Bio-Resource Research and Development, Graduate School of Medicine, Kyoto University, 46-29, Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8304, Japan
- KBBM Inc, 46-29, Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8304, Japan
| | - Jumpei Kondo
- Department of Clinical Bio-Resource Research and Development, Graduate School of Medicine, Kyoto University, 46-29, Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8304, Japan
- Division of Health Sciences, Department of Molecular Biology and Clinical Investigation, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Kunishige Onuma
- Department of Clinical Bio-Resource Research and Development, Graduate School of Medicine, Kyoto University, 46-29, Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8304, Japan
| | - Roberto Coppo
- Department of Clinical Bio-Resource Research and Development, Graduate School of Medicine, Kyoto University, 46-29, Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8304, Japan
| | - Yukiko Mori
- Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Manabu Muto
- Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Yuichiro Kikawa
- Department of Breast Surgery, Kansai Medical University, Hirakata, Osaka, 573-1191, Japan
| | - Manami Tada
- Department of Breast Surgery, Kansai Medical University, Hirakata, Osaka, 573-1191, Japan
| | - Tomoharu Sugie
- Department of Breast Surgery, Kansai Medical University, Hirakata, Osaka, 573-1191, Japan
| | - Masahiro Inoue
- Department of Clinical Bio-Resource Research and Development, Graduate School of Medicine, Kyoto University, 46-29, Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8304, Japan.
- Department of Clinical Bio-Resource Research and Development, Graduate School of Medicine, Kyoto University, Med-Pharm Collaboration Building 503, Shimoadachi-cho 46-29, Sakyou-ku, Kyoto, 606-8304, Japan.
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20
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Liu Q, Li G, Baladandayuthapani V. Pan-Cancer Drug Response Prediction Using Integrative Principal Component Regression. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.03.560366. [PMID: 37873111 PMCID: PMC10592913 DOI: 10.1101/2023.10.03.560366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
The pursuit of precision oncology heavily relies on large-scale genomic and pharmacological data garnered from preclinical cancer model systems such as cell lines. While cell lines are instrumental in understanding the interplay between genomic programs and drug response, it well-established that they are not fully representative of patient tumors. Development of integrative methods that can systematically assess the commonalities between patient tumors and cell-lines can help bridge this gap. To this end, we introduce the Integrative Principal Component Regression (iPCR) model which uncovers both joint and model-specific structured variations in the genomic data of cell lines and patient tumors through matrix decompositions. The extracted joint variation is then used to predict patient drug responses based on the pharmacological data from preclinical models. Moreover, the interpretability of our model allows for the identification of key driver genes and pathways associated with the treatment-specific response in patients across multiple cancers. We demonstrate that the outputs of the iPCR model can assist in inferring both model-specific and shared co-expression networks between cell lines and patients. We show that iPCR performs favorably compared to competing approaches in predicting patient drug responses, in both simulation studies and real-world applications, in addition to identifying key genomic drivers of cancer drug responses.
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21
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Hong R, Lim SC, Lee TB, Han SI. Anticancer Effect of Gallic Acid on Acidity-Induced Invasion of MCF7 Breast Cancer Cells. Nutrients 2023; 15:3596. [PMID: 37630786 PMCID: PMC10458441 DOI: 10.3390/nu15163596] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 08/14/2023] [Accepted: 08/15/2023] [Indexed: 08/27/2023] Open
Abstract
The acidic tumor environment has emerged as a crucial factor influencing the metastatic potential of cancer. We investigated the effect of an acidic environment on the acquisition of metastatic properties in MCF7 breast cancer cells and explored the inhibitory effects of gallic acid. Prolonged exposure to acidic culture conditions (over 12 weeks at pH 6.4) induced the acquisition of migratory and invasive properties in MCF7 cells, accompanied by increased expression of Matrix Metalloproteinase 2 and 9 (MMP2 and MMP9, respectively), together with alterations in E-cadherin, vimentin, and epithelial-to-mesenchymal transition markers. Gallic acid effectively inhibited the survival of acidity-adapted MCF7 (MCF7-6.4/12w) cells at high concentrations (>30 μM) and reduced metastatic characteristics induced by acidic conditions at low concentration ranges (5-20 μM). Moreover, gallic acid suppressed the PI3K/Akt pathway and the nuclear accumulation of β-catenin, which were elevated in MCF7-6.4/12w cells. These findings highlight the potential of gallic acid as a promising therapeutic agent for metastatic traits in breast cancer cells under acidic conditions.
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Affiliation(s)
- Ran Hong
- Department of Pathology, College of Medicine, Chosun University, Gwangju 61452, Republic of Korea; (R.H.); (S.-C.L.)
| | - Sung-Chul Lim
- Department of Pathology, College of Medicine, Chosun University, Gwangju 61452, Republic of Korea; (R.H.); (S.-C.L.)
| | - Tae-Bum Lee
- Division of Premedical Science, College of Medicine, Chosun University, Gwangju 61452, Republic of Korea;
| | - Song-Iy Han
- Division of Premedical Science, College of Medicine, Chosun University, Gwangju 61452, Republic of Korea;
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22
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Pierzynska-Mach A, Cainero I, Oneto M, Ferrando-May E, Lanzanò L, Diaspro A. Imaging-based study demonstrates how the DEK nanoscale distribution differentially correlates with epigenetic marks in a breast cancer model. Sci Rep 2023; 13:12749. [PMID: 37550322 PMCID: PMC10406876 DOI: 10.1038/s41598-023-38685-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 07/12/2023] [Indexed: 08/09/2023] Open
Abstract
Epigenetic dysregulation of chromatin is one of the hallmarks of cancer development and progression, and it is continuously investigated as a potential general bio-marker of this complex disease. One of the nuclear factors involved in gene regulation is the unique DEK protein-a histone chaperon modulating chromatin topology. DEK expression levels increase significantly from normal to cancer cells, hence raising the possibility of using DEK as a tumor marker. Although DEK is known to be implicated in epigenetic and transcriptional regulation, the details of these interactions and their relevance in cancer development remain largely elusive. In this work, we investigated the spatial correlation between the nuclear distribution of DEK and chromatin patterns-alongside breast cancer progression-leveraging image cross-correlation spectroscopy (ICCS) coupled with Proximity Ligation Assay (PLA) analysis. We performed our study on the model based on three well-established human breast cell lines to consider this tumor's heterogeneity (MCF10A, MCF7, and MDA-MB-231 cells). Our results show that overexpression of DEK correlates with the overall higher level of spatial proximity between DEK and histone marks corresponding to gene promoters regions (H3K9ac, H3K4me3), although it does not correlate with spatial proximity between DEK and gene enhancers (H3K27ac). Additionally, we observed that colocalizing fractions of DEK and histone marks are lower for the non-invasive cell subtype than for the highly invasive cell line (MDA-MB-231). Thus, this study suggests that the role of DEK on transcriptionally active chromatin regions varies depending on the subtype of the breast cancer cell line.
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Affiliation(s)
| | - Isotta Cainero
- Nanoscopy and NIC @ IIT, Istituto Italiano di Tecnologia, Via Enrico Melen, 83, 16152, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, Italy
| | - Michele Oneto
- Nanoscopy and NIC @ IIT, Istituto Italiano di Tecnologia, Via Enrico Melen, 83, 16152, Genoa, Italy
| | - Elisa Ferrando-May
- Department of Biology, University of Konstanz, Konstanz, Germany
- German Cancer Research Center, Heidelberg, Germany
| | - Luca Lanzanò
- Nanoscopy and NIC @ IIT, Istituto Italiano di Tecnologia, Via Enrico Melen, 83, 16152, Genoa, Italy
- Department of Physics and Astronomy, University of Catania, Catania, Italy
| | - Alberto Diaspro
- Nanoscopy and NIC @ IIT, Istituto Italiano di Tecnologia, Via Enrico Melen, 83, 16152, Genoa, Italy.
- DIFILAB, Department of Physics, University of Genoa, Genoa, Italy.
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23
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Udu-Ituma S, Adélaïde J, Le TK, Omabe K, Finetti P, Paris C, Guille A, Bertucci F, Birnbaum D, Rocchi P, Chaffanet M. ZNF703 mRNA-Targeting Antisense Oligonucleotide Blocks Cell Proliferation and Induces Apoptosis in Breast Cancer Cell Lines. Pharmaceutics 2023; 15:1930. [PMID: 37514116 PMCID: PMC10384502 DOI: 10.3390/pharmaceutics15071930] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 06/29/2023] [Accepted: 06/30/2023] [Indexed: 07/30/2023] Open
Abstract
The luminal B molecular subtype of breast cancers (BC) accounts for more than a third of BCs and is associated with aggressive clinical behavior and poor prognosis. The use of endocrine therapy in BC treatment has significantly contributed to the decrease in the number of deaths in recent years. However, most BC patients with prolonged exposure to estrogen receptor (ER) selective modulators such as tamoxifen develop resistance and become non-responsive over time. Recent studies have implicated overexpression of the ZNF703 gene in BC resistance to endocrine drugs, thereby highlighting ZNF703 inhibition as an attractive modality in BC treatment, especially luminal B BCs. However, there is no known inhibitor of ZNF703 due to its nuclear association and non-enzymatic activity. Here, we have developed an antisense oligonucleotide (ASO) against ZNF703 mRNA and shown that it downregulates ZNF703 protein expression. ZNF703 inhibition decreased cell proliferation and induced apoptosis. Combined with cisplatin, the anti-cancer effects of ZNF703-ASO9 were improved. Moreover, our work shows that ASO technology may be used to increase the number of targetable cancer genes.
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Affiliation(s)
- Sandra Udu-Ituma
- Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
- Department of Biology, Alex Ekwueme Federal University Ndufu-Alike Ikwo, Abakaliki P.M.B. 1010, Ebonyi State, Nigeria
- European Center for Research in Medical Imaging, Aix-Marseille University, 13005 Marseille, France
| | - José Adélaïde
- Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
| | - Thi Khanh Le
- Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
- European Center for Research in Medical Imaging, Aix-Marseille University, 13005 Marseille, France
| | - Kenneth Omabe
- Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
| | - Pascal Finetti
- Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
| | - Clément Paris
- Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
| | - Arnaud Guille
- Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
| | - François Bertucci
- Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
| | - Daniel Birnbaum
- Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
| | - Palma Rocchi
- Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
- European Center for Research in Medical Imaging, Aix-Marseille University, 13005 Marseille, France
| | - Max Chaffanet
- Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
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24
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Couto JP, Vulin M, Jehanno C, Coissieux M, Hamelin B, Schmidt A, Ivanek R, Sethi A, Bräutigam K, Frei AL, Hager C, Manivannan M, Gómez‐Miragaya J, Obradović MMS, Varga Z, Koelzer VH, Mertz KD, Bentires‐Alj M. Nicotinamide N-methyltransferase sustains a core epigenetic program that promotes metastatic colonization in breast cancer. EMBO J 2023; 42:e112559. [PMID: 37259596 PMCID: PMC10308372 DOI: 10.15252/embj.2022112559] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 04/25/2023] [Accepted: 05/05/2023] [Indexed: 06/02/2023] Open
Abstract
Metastatic colonization of distant organs accounts for over 90% of deaths related to solid cancers, yet the molecular determinants of metastasis remain poorly understood. Here, we unveil a mechanism of colonization in the aggressive basal-like subtype of breast cancer that is driven by the NAD+ metabolic enzyme nicotinamide N-methyltransferase (NNMT). We demonstrate that NNMT imprints a basal genetic program into cancer cells, enhancing their plasticity. In line, NNMT expression is associated with poor clinical outcomes in patients with breast cancer. Accordingly, ablation of NNMT dramatically suppresses metastasis formation in pre-clinical mouse models. Mechanistically, NNMT depletion results in a methyl overflow that increases histone H3K9 trimethylation (H3K9me3) and DNA methylation at the promoters of PR/SET Domain-5 (PRDM5) and extracellular matrix-related genes. PRDM5 emerged in this study as a pro-metastatic gene acting via induction of cancer-cell intrinsic transcription of collagens. Depletion of PRDM5 in tumor cells decreases COL1A1 deposition and impairs metastatic colonization of the lungs. These findings reveal a critical activity of the NNMT-PRDM5-COL1A1 axis for cancer cell plasticity and metastasis in basal-like breast cancer.
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Affiliation(s)
- Joana Pinto Couto
- Department of Biomedicine, University Hospital BaselUniversity of BaselBaselSwitzerland
- Department of SurgeryUniversity Hospital BaselBaselSwitzerland
- Friedrich Miescher Institute for Biomedical ResearchBaselSwitzerland
| | - Milica Vulin
- Department of Biomedicine, University Hospital BaselUniversity of BaselBaselSwitzerland
- Department of SurgeryUniversity Hospital BaselBaselSwitzerland
- Friedrich Miescher Institute for Biomedical ResearchBaselSwitzerland
| | - Charly Jehanno
- Department of Biomedicine, University Hospital BaselUniversity of BaselBaselSwitzerland
- Department of SurgeryUniversity Hospital BaselBaselSwitzerland
| | - Marie‐May Coissieux
- Department of Biomedicine, University Hospital BaselUniversity of BaselBaselSwitzerland
- Department of SurgeryUniversity Hospital BaselBaselSwitzerland
- Friedrich Miescher Institute for Biomedical ResearchBaselSwitzerland
| | - Baptiste Hamelin
- Department of Biomedicine, University Hospital BaselUniversity of BaselBaselSwitzerland
- Department of SurgeryUniversity Hospital BaselBaselSwitzerland
| | - Alexander Schmidt
- Proteomics Core Facility, BiozentrumUniversity of BaselBaselSwitzerland
| | - Robert Ivanek
- Department of Biomedicine, University Hospital BaselUniversity of BaselBaselSwitzerland
- Swiss Institute of BioinformaticsBaselSwitzerland
| | - Atul Sethi
- Department of Biomedicine, University Hospital BaselUniversity of BaselBaselSwitzerland
- Department of SurgeryUniversity Hospital BaselBaselSwitzerland
- Friedrich Miescher Institute for Biomedical ResearchBaselSwitzerland
- Swiss Institute of BioinformaticsBaselSwitzerland
| | - Konstantin Bräutigam
- Computational and Translational Pathology Group, Department of Pathology and Molecular Pathology, University Hospital ZurichUniversity of ZurichZürichSwitzerland
- Institute of PathologyUniversity of BernBernSwitzerland
| | - Anja L Frei
- Computational and Translational Pathology Group, Department of Pathology and Molecular Pathology, University Hospital ZurichUniversity of ZurichZürichSwitzerland
| | - Carolina Hager
- Department of Biomedicine, University Hospital BaselUniversity of BaselBaselSwitzerland
- Department of SurgeryUniversity Hospital BaselBaselSwitzerland
| | - Madhuri Manivannan
- Department of Biomedicine, University Hospital BaselUniversity of BaselBaselSwitzerland
- Department of SurgeryUniversity Hospital BaselBaselSwitzerland
| | - Jorge Gómez‐Miragaya
- Department of Biomedicine, University Hospital BaselUniversity of BaselBaselSwitzerland
- Department of SurgeryUniversity Hospital BaselBaselSwitzerland
| | - Milan MS Obradović
- Department of Biomedicine, University Hospital BaselUniversity of BaselBaselSwitzerland
- Department of SurgeryUniversity Hospital BaselBaselSwitzerland
- Friedrich Miescher Institute for Biomedical ResearchBaselSwitzerland
| | - Zsuzsanna Varga
- Computational and Translational Pathology Group, Department of Pathology and Molecular Pathology, University Hospital ZurichUniversity of ZurichZürichSwitzerland
| | - Viktor H Koelzer
- Computational and Translational Pathology Group, Department of Pathology and Molecular Pathology, University Hospital ZurichUniversity of ZurichZürichSwitzerland
| | - Kirsten D Mertz
- Institute of PathologyCantonal Hospital BasellandLiestalSwitzerland
| | - Mohamed Bentires‐Alj
- Department of Biomedicine, University Hospital BaselUniversity of BaselBaselSwitzerland
- Department of SurgeryUniversity Hospital BaselBaselSwitzerland
- Friedrich Miescher Institute for Biomedical ResearchBaselSwitzerland
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25
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Sang R, Fan R, Deng A, Gou J, Lin R, Zhao T, Hai Y, Song J, Liu Y, Qi B, Du G, Cheng M, Wei G. Degradation of Hexokinase 2 Blocks Glycolysis and Induces GSDME-Dependent Pyroptosis to Amplify Immunogenic Cell Death for Breast Cancer Therapy. J Med Chem 2023. [PMID: 37376788 DOI: 10.1021/acs.jmedchem.3c00118] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/29/2023]
Abstract
Hexokinase 2 (HK2) is the principal rate-limiting enzyme in the aerobic glycolysis pathway and determines the quantity of glucose entering glycolysis. However, the current HK2 inhibitors have poor activity, so we used proteolysis-targeting chimera (PROTAC) technology to design and synthesize novel HK2 degraders. Among them, C-02 has the best activity to degrade HK2 protein and inhibit breast cancer cells. It is demonstrated that C-02 could block glycolysis, cause mitochondrial damage, and then induce GSDME-dependent pyroptosis. Furthermore, pyroptosis induces cell immunogenic death (ICD) and activates antitumor immunity, thus improving antitumor immunotherapy in vitro and in vivo. These findings show that the degradation of HK2 can effectively inhibit the aerobic metabolism of breast cancer cells, thereby inhibiting their malignant proliferation and reversing the immunosuppressive microenvironment.
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Affiliation(s)
- Ruoxi Sang
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen, Guangdong 518057, China
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Renming Fan
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen, Guangdong 518057, China
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Aohua Deng
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen, Guangdong 518057, China
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Jiakui Gou
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Ruizhuo Lin
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen, Guangdong 518057, China
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Ting Zhao
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Yongrui Hai
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen, Guangdong 518057, China
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Junke Song
- Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Yang Liu
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Bing Qi
- Institute of Oncology, The Second Affiliated Hospital, Xi'an Medical University, Xi'an, Shaanxi 710038, China
| | - Guanhua Du
- Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Maosheng Cheng
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Gaofei Wei
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen, Guangdong 518057, China
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
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26
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Zhang D, Zhang C, Zhu Y, Xie H, Yue C, Li M, Wei W, Peng Y, Yin G, Guo Y, Guan Y. Recruitment of transcription factor ETS1 to activated accessible regions promotes the transcriptional program of cilia genes. Nucleic Acids Res 2023:gkad506. [PMID: 37326025 PMCID: PMC10359609 DOI: 10.1093/nar/gkad506] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 05/25/2023] [Accepted: 06/01/2023] [Indexed: 06/17/2023] Open
Abstract
Defects in cilia genes, which are critical for cilia formation and function, can cause complicated ciliopathy syndromes involving multiple organs and tissues; however, the underlying regulatory mechanisms of the networks of cilia genes in ciliopathies remain enigmatic. Herein, we have uncovered the genome-wide redistribution of accessible chromatin regions and extensive alterations of expression of cilia genes during Ellis-van Creveld syndrome (EVC) ciliopathy pathogenesis. Mechanistically, the distinct EVC ciliopathy-activated accessible regions (CAAs) are shown to positively regulate robust changes in flanking cilia genes, which are a key requirement for cilia transcription in response to developmental signals. Moreover, a single transcription factor, ETS1, can be recruited to CAAs, leading to prominent chromatin accessibility reconstruction in EVC ciliopathy patients. In zebrafish, the collapse of CAAs driven by ets1 suppression subsequently causes defective cilia proteins, resulting in body curvature and pericardial oedema. Our results depict a dynamic landscape of chromatin accessibility in EVC ciliopathy patients, and uncover an insightful role for ETS1 in controlling the global transcriptional program of cilia genes by reprogramming the widespread chromatin state.
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Affiliation(s)
- Donghui Zhang
- Zhanjiang Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, PR China
| | - Chong Zhang
- Zhanjiang Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, PR China
| | - Yanmei Zhu
- Zhanjiang Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, PR China
| | - Haixia Xie
- Precision Clinical Laboratory, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, PR China
| | - Caifeng Yue
- Precision Clinical Laboratory, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, PR China
- Department of Laboratory Medicine, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, PR China
| | - Mingfeng Li
- Zhanjiang Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, PR China
| | - Wenlu Wei
- Zhanjiang Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, PR China
| | - Yu Peng
- Pediatric Intensive Care Unit Central, People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, PR China
| | - Guibin Yin
- Department of Orthopedics, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, PR China
| | - Yunmiao Guo
- Zhanjiang Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, PR China
| | - Yiting Guan
- Zhanjiang Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang 524045, PR China
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27
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Tundidor I, Seijo-Vila M, Blasco-Benito S, Rubert-Hernández M, Adámez S, Andradas C, Manzano S, Álvarez-López I, Sarasqueta C, Villa-Morales M, González-Lois C, Ramírez-Medina E, Almoguera B, Sánchez-López AJ, Bindila L, Hamann S, Arnold N, Röcken C, Heras-Murillo I, Sancho D, Moreno-Bueno G, Caffarel MM, Guzmán M, Sánchez C, Pérez-Gómez E. Identification of fatty acid amide hydrolase as a metastasis suppressor in breast cancer. Nat Commun 2023; 14:3130. [PMID: 37253733 DOI: 10.1038/s41467-023-38750-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 05/11/2023] [Indexed: 06/01/2023] Open
Abstract
Clinical management of breast cancer (BC) metastasis remains an unmet need as it accounts for 90% of BC-associated mortality. Although the luminal subtype, which represents >70% of BC cases, is generally associated with a favorable outcome, it is susceptible to metastatic relapse as late as 15 years after treatment discontinuation. Seeking therapeutic approaches as well as screening tools to properly identify those patients with a higher risk of recurrence is therefore essential. Here, we report that the lipid-degrading enzyme fatty acid amide hydrolase (FAAH) is a predictor of long-term survival in patients with luminal BC, and that it blocks tumor progression and lung metastasis in cell and mouse models of BC. Together, our findings highlight the potential of FAAH as a biomarker with prognostic value in luminal BC and as a therapeutic target in metastatic disease.
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Affiliation(s)
- Isabel Tundidor
- Department of Biochemistry and Molecular Biology, Complutense University, Madrid, Spain
- Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain
| | - Marta Seijo-Vila
- Department of Biochemistry and Molecular Biology, Complutense University, Madrid, Spain
- Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain
| | - Sandra Blasco-Benito
- Department of Biochemistry and Molecular Biology, Complutense University, Madrid, Spain
- Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain
| | - María Rubert-Hernández
- Department of Biochemistry and Molecular Biology, Complutense University, Madrid, Spain
- Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain
| | - Sandra Adámez
- Department of Biochemistry and Molecular Biology, Complutense University, Madrid, Spain
| | - Clara Andradas
- Brain Tumor Research Program, Telethon Kids Institute, Nedlands, WA, Australia
- Centre for Child Health Research, University of Western Australia, Nedlands, WA, Australia
| | - Sara Manzano
- Breast Cancer Group, Oncology Area, Biodonostia Health Research Institute, San Sebastián, Spain
| | - Isabel Álvarez-López
- Breast Cancer Group, Oncology Area, Biodonostia Health Research Institute, San Sebastián, Spain
- Gipuzkoa Cancer Unit, OSI Donostialdea-Onkologikoa Foundation, San Sebastián, Spain
| | - Cristina Sarasqueta
- Unit of Information and Healthcare Results, OSI Donostialdea, Biodonostia Health Research Institute, San Sebastián, Spain
- Methodological Support Unit, Biodonostia Health Research Institute, San Sebastián, Spain
| | - María Villa-Morales
- Centro de Biología Molecular Severo Ochoa (CBMSO) (CSIC-UAM), Madrid, Spain
- Department of Biology, Autonomous University of Madrid, Madrid, Spain
| | - Carmen González-Lois
- Department of Pathology, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain
| | - Esther Ramírez-Medina
- Department of Obstetrics & Gynecology, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain
| | - Belén Almoguera
- Department of Obstetrics & Gynecology, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain
| | - Antonio J Sánchez-López
- Biobank Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana (IDIPHISA), Madrid, Spain
| | - Laura Bindila
- Clinical Lipidomics Unit, Institute of Physiological Chemistry, University Medical Center, Mainz, Germany
| | - Sigrid Hamann
- Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Norbert Arnold
- Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Christoph Röcken
- Institute of Pathology, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Ignacio Heras-Murillo
- Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - David Sancho
- Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Gema Moreno-Bueno
- MD Anderson International Foundation; Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM); Department of Biochemistry, Autonomous University of Madrid; Instituto de Investigación Hospital Universitario La Paz (IdiPaz); Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - María M Caffarel
- Breast Cancer Group, Oncology Area, Biodonostia Health Research Institute, San Sebastián, Spain
- Ikerbasque-Basque Foundation for Science, Bilbao, Spain
| | - Manuel Guzmán
- Department of Biochemistry and Molecular Biology, Complutense University, Madrid, Spain
- Instituto Ramón y Cajal de Investigación Sanitaria y Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Cristina Sánchez
- Department of Biochemistry and Molecular Biology, Complutense University, Madrid, Spain.
- Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain.
| | - Eduardo Pérez-Gómez
- Department of Biochemistry and Molecular Biology, Complutense University, Madrid, Spain.
- Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain.
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Li C, Geng C. GLIS Family Zinc Finger 3 Promotes Triple-Negative Breast Cancer Progression by Inducing Cell Proliferation, Migration and Invasion, and Activating the NF-κB Signaling Pathway. Biol Pharm Bull 2023; 46:209-218. [PMID: 36724950 DOI: 10.1248/bpb.b22-00595] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Triple-negative breast cancer (TNBC) puts a great threat to women's health. GLIS family zinc finger 3 (GLIS3) belongs to the GLI transcription factor family and acts as a critical factor in cancer progression. Nevertheless, the part of GLIS3 played in TNBC is not known. Immunohistochemical (IHC) staining analysis displayed that GLIS3 was highly expressed in TNBC tissues. The effect of GLIS3 on the malignant phenotype of TNBC was tested in two different cell lines according to GLIS3 regulation. Upregulation of GLIS3 promoted the proliferation, migration, and invasion of TNBC cell lines, whereas the knockdown of GLIS3 suppressed these tumor activities. Inhibition of GLIS3 induced TNBC cell apoptosis. Furthermore, study as immunofluorescence and electrophoretic mobility shift assay confirmed that the nuclear factor-κB (NF-κB) signaling pathway activated by GLIS3 played an important role in TNBC cells' malignant phenotype. In conclusion, the present work demonstrated that GLIS3 acts as a crucial element in TNBC progression via activating the NF-κB signaling pathway. Accordingly, above mentioned findings indicated that modulation of GLIS3 expression is a potential tactic to interfere with the progression of TNBC.
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Affiliation(s)
- Chenhao Li
- Diagnostic and Therapeutic Center for Breast Disease, The Fourth Hospital of Hebei Medical University.,The Second Department of Thyroid and Breast Surgery, Cangzhou Central Hospital
| | - Cuizhi Geng
- Diagnostic and Therapeutic Center for Breast Disease, The Fourth Hospital of Hebei Medical University.,Key Laboratory of Molecular Medicine of Breast Cancer in Hebei
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Sagara A, Miura S, Kobinata A, Naganawa R, Yaginuma S, Saito S, Saito R, Kominato H, Yumoto T, Sato F. COL8A1 enhances the invasion/metastasis in MDA-MB-231 cells via the induction of IL1B and MMP1 expression. Biochem Biophys Res Commun 2023; 642:145-153. [PMID: 36577251 DOI: 10.1016/j.bbrc.2022.12.046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high probability of metastasis and a lack of specific targets and targeted therapeutics. Previously, we have reported that COL8A1, which is highly expressed in the mesenchymal stem-like (MSL) subtype of TNBC, facilitates TNBC growth via FAK/Src activation. Furthermore, we have found that COL8A1 enhances the invasion and metastasis of MDA-MB-231 cells, classified into MSL. However, the mechanism of invasion and metastasis by COL8A1 remains unclear. Here, we investigated the biological function of COL8A1 on the invasion and metastasis of MDA-MB-231 cells. METHODS The invasion and metastasis of MDA-MB-231 cells were evaluated using three-dimensional (3D) culture methods and xenograft mouse models. DNA microarray analysis examined the gene expression in COL8A1-overexpressing MDA-MB-231 cells and control cells. Gene expression was verified using RT-qPCR. RESULTS COL8A1-deficient cells showed little or no metastasis, whereas forced expression of COL8A1 in MDA-MB-231 cells, the MSL subtype of TNBC cell lines, significantly promoted distant metastasis after tumor resection. As with in vivo, 3D invasion assay revealed that COL8A1 increased the invasion capacity of MDA-MB-231 and Hs578T cells, classified into the MSL subtype of TNBC. DNA microarray analysis for COL8A1-overexpressing cells indicated that COL8A1 induces interleukin 1B (IL1B) and matrix metalloproteinase-1 (MMP1) expression, both of which are correlated with COL8A1 expression in the mesenchymal subtypes of TNBC, and the Kaplan-Meier plotter provided evidence that the prognosis in the MSL subtype was strongly associated with both gene expressions and COL8A1 expression. Pharmacological inhibitor treatment showed that COL8A1 regulated IL1B and MMP1 expression through a different pathway. Moreover, the knockdown of each gene expression reduced the invasion capacity of COL8A1-overexpressing MDA-MB-231 and Hs578T cells. CONCLUSION Our findings indicate that COL8A1-induced IL1B and MMP1 enhanced the invasion and metastasis of the MSL subtype of TNBC. Considering our previous findings that COL8A1 promotes tumor growth, COL8A1 may be a prognostic and practical therapeutic target in TNBC.
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Affiliation(s)
- Atsunobu Sagara
- Laboratory of Analytical Pathophysiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Shotaro Miura
- Laboratory of Analytical Pathophysiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Akinori Kobinata
- Laboratory of Analytical Pathophysiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Risa Naganawa
- Laboratory of Analytical Pathophysiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Saki Yaginuma
- Laboratory of Analytical Pathophysiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Suguru Saito
- Laboratory of Analytical Pathophysiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Rintaro Saito
- Laboratory of Analytical Pathophysiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Hidenori Kominato
- Laboratory of Analytical Pathophysiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Tetsuro Yumoto
- Laboratory of Analytical Pathophysiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Fumiaki Sato
- Laboratory of Analytical Pathophysiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
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Parikh AS, Wizel A, Davis D, Lefranc-Torres A, Rodarte-Rascon AI, Miller LE, Emerick KS, Varvares MA, Deschler DG, Faquin WC, Aster JC, Lin DT, Bernstein BE, Drier Y, Puram SV. Single-cell RNA sequencing identifies a paracrine interaction that may drive oncogenic notch signaling in human adenoid cystic carcinoma. Cell Rep 2022; 41:111743. [PMID: 36450256 PMCID: PMC9760094 DOI: 10.1016/j.celrep.2022.111743] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 08/11/2022] [Accepted: 11/07/2022] [Indexed: 12/02/2022] Open
Abstract
Salivary adenoid cystic carcinoma (ACC) is a rare, biologically unique biphasic tumor that consists of malignant myoepithelial and luminal cells. MYB and Notch signaling have been implicated in ACC pathophysiology, but in vivo descriptions of these two programs in human tumors and investigation into their active coordination remain incomplete. We utilize single-cell RNA sequencing to profile human head and neck ACC, including a comparison of primary ACC with a matched local recurrence. We define expression heterogeneity in these rare tumors, uncovering diversity in myoepithelial and luminal cell expression. We find differential expression of Notch ligands DLL1, JAG1, and JAG2 in myoepithelial cells, suggesting a paracrine interaction that may support oncogenic Notch signaling. We validate this selective expression in three published cohorts of patients with ACC. Our data provide a potential explanation for the biphasic nature of low- and intermediate-grade ACC and may help direct new therapeutic strategies against these tumors.
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Affiliation(s)
- Anuraag S Parikh
- Department of Otolaryngology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
| | - Avishai Wizel
- The Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Daniel Davis
- The Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | | | | | - Lauren E Miller
- Department of Otolaryngology, Massachusetts Eye and Ear, Boston, MA 02114, USA; Department of Otolaryngology, Harvard Medical School, Boston, MA 02115, USA
| | - Kevin S Emerick
- Department of Otolaryngology, Massachusetts Eye and Ear, Boston, MA 02114, USA; Department of Otolaryngology, Harvard Medical School, Boston, MA 02115, USA
| | - Mark A Varvares
- Department of Otolaryngology, Massachusetts Eye and Ear, Boston, MA 02114, USA; Department of Otolaryngology, Harvard Medical School, Boston, MA 02115, USA
| | - Daniel G Deschler
- Department of Otolaryngology, Massachusetts Eye and Ear, Boston, MA 02114, USA; Department of Otolaryngology, Harvard Medical School, Boston, MA 02115, USA
| | - William C Faquin
- Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
| | - Jon C Aster
- Department of Pathology, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Derrick T Lin
- Department of Otolaryngology, Massachusetts Eye and Ear, Boston, MA 02114, USA; Department of Otolaryngology, Harvard Medical School, Boston, MA 02115, USA
| | - Bradley E Bernstein
- Department of Pathology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Yotam Drier
- The Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
| | - Sidharth V Puram
- Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
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The POLR3G Subunit of Human RNA Polymerase III Regulates Tumorigenesis and Metastasis in Triple-Negative Breast Cancer. Cancers (Basel) 2022; 14:cancers14235732. [PMID: 36497214 PMCID: PMC9735567 DOI: 10.3390/cancers14235732] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/10/2022] [Accepted: 11/14/2022] [Indexed: 11/24/2022] Open
Abstract
RNA polymerase (Pol) III transcribes short untranslated RNAs that contribute to the regulation of gene expression. Two isoforms of human Pol III have been described that differ by the presence of the POLR3G/RPC32α or POLR3GL/RPC32β subunits. POLR3G was found to be expressed in embryonic stem cells and at least a subset of transformed cells, whereas POLR3GL shows a ubiquitous expression pattern. Here, we demonstrate that POLR3G is specifically overexpressed in clinical samples of triple-negative breast cancer (TNBC) but not in other molecular subtypes of breast cancer. POLR3G KO in the MDA-MB231 TNBC cell line dramatically reduces anchorage-independent growth and invasive capabilities in vitro. In addition, the POLR3G KO impairs tumor growth and metastasis formation of orthotopic xenografts in mice. Moreover, KO of POLR3G induces expression of the pioneer transcription factor FOXA1 and androgen receptor. In contrast, the POLR3G KO neither alters proliferation nor the expression of epithelial-mesenchymal transition marker genes. These data demonstrate that POLR3G expression is required for TNBC tumor growth, invasiveness and dissemination and that its deletion affects triple-negative breast cancer-specific gene expression.
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Wang Y, Huang D, Song T, Qi X, Li M, Zhang H, Liu Y, Yang M. Andrographolide elevates tumor necrosis factor-related apoptosis-inducing ligand lethality through reactive oxygen species accumulation and gasdermin E cleavage in breast cancer cells. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 40:11. [PMID: 36352155 DOI: 10.1007/s12032-022-01878-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/23/2022] [Indexed: 11/10/2022]
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is selectively lethal to cancer cells and harmless to normal cells, making it a potential agent for cancer therapy. However, some breast cancer cells are resistant to TRAIL. This study revealed that andrographolide (Andro), an extract from Andrographis paniculate, a natural compound, sensitized breast cancer cells to TRAIL-induced tumor suppression; it identified apoptosis-associated protein regulation, reactive oxygen species accumulation, mitochondria membrane potential disruption, caspase cascade activation, and gasdermin-E cleavage to be involved in the tumor lethality mediated by Andro combined with TRAIL treatment. The flow cytometry results showed the combination of Andro and TRAIL repressed breast cancer cells by cell death induction, and the assessment of combined index indicated that the combined treatment with Andro and TRAIL repressed breast cancer cells synergistically. Blotting results displayed Andro and TRAIL combination elevated TRAIL-associated receptors, death receptors 4 and 5, at protein levels. These results provided critical insight into breast cancer patients' therapy and exploration direction for TRAIL clinical application.
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Affiliation(s)
- Yueyuan Wang
- Department of Breast Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, People's Republic of China
| | - Dan Huang
- Department of Breast Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, People's Republic of China
| | - Tingting Song
- Department of Breast Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, People's Republic of China
| | - Xiaoyan Qi
- Department of Breast Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, People's Republic of China
| | - Mingxi Li
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, People's Republic of China
| | - Hui Zhang
- Department of Breast Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, People's Republic of China
| | - Yang Liu
- Department of Breast Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, People's Republic of China
| | - Ming Yang
- Department of Breast Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, People's Republic of China.
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Szabova L, Gordon MB, Lu L, Pate N, Bassel L, Iacovelli AJ, Karim B, Homan PJ, Householder DB, Guerin TM, Burkett S, Day AM, Custer W, Weaver Ohler Z. Loss of Brca1 and Trp53 in adult mouse mammary ductal epithelium results in development of hormone receptor-positive or hormone receptor-negative tumors, depending on inactivation of Rb family proteins. Breast Cancer Res 2022; 24:75. [PMID: 36333737 PMCID: PMC9636824 DOI: 10.1186/s13058-022-01566-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 10/08/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Breast cancer is a heterogenous disease with several histological and molecular subtypes. Models that represent these subtypes are essential for translational research aimed at improving clinical strategy for targeted therapeutics. METHODS Different combinations of genetic aberrations (Brca1 and Trp53 loss, and inhibition of proteins of the Rb family) were induced in the mammary gland by injection of adenovirus expressing Cre recombinase into the mammary ducts of adult genetically engineered mice. Mammary tumors with different genetic aberrations were classified into molecular subtypes based on expression of molecular markers and RNAseq analysis. In vitro potency assays and Western blots were used to examine their drug sensitivities. RESULTS Induction of Brca1 and Trp53 loss in mammary ductal epithelium resulted in development of basal-like hormone receptor (HR)-negative mammary tumors. Inhibition of Rb and Trp53 loss or the combination of Rb, Trp53 and Brca1 aberrations resulted in development of luminal ductal carcinoma positive for ER, PR, and Her2 expression. HR positivity in tumors with Rb, Trp53 and Brca1 aberrations indicated that functionality of the Rb pathway rather than Brca1 status affected HR status in these models. Mammary tumor gene expression profiles recapitulated human basal-like or luminal B breast cancer signatures, but HR-positive luminal cancer models were endocrine resistant and exhibited upregulation of PI3K signaling and sensitivity to this pathway inhibition. Furthermore, both tumor subtypes were resistant to CDK4/6 inhibition. CONCLUSIONS Examination of molecular expression profiles and drug sensitivities of tumors indicate that these breast cancer models can be utilized as a translational platform for evaluation of targeted combinations to improve chemotherapeutic response in patients that no longer respond to hormone therapy or that are resistant to CDK4/6 inhibition.
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Affiliation(s)
- Ludmila Szabova
- Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA.
| | - Melanie B Gordon
- Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA
| | - Lucy Lu
- Center for Advanced Preclinical Research, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA
| | - Nathan Pate
- Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA
- Sanofi,Global Discovery Pathology, Translational In Vivo Models Platform, Framingham, MA, USA
| | - Laura Bassel
- Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA
| | - Anthony J Iacovelli
- Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA
- Genentech, Inc., South San Francisco, CA, USA
| | - Baktiar Karim
- Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA
- Molecular Histopathology Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA
| | - Philip J Homan
- CCR Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Deborah B Householder
- Center for Advanced Preclinical Research, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA
| | - Theresa M Guerin
- Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA
| | - Sandra Burkett
- Molecular Cytogenetics Core Facility, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA
| | - Amanda M Day
- Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA
| | - Wendi Custer
- Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA
| | - Zoe Weaver Ohler
- Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA.
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Bi-EB: Empirical Bayesian Biclustering for Multi-Omics Data Integration Pattern Identification among Species. Genes (Basel) 2022; 13:genes13111982. [DOI: 10.3390/genes13111982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 09/20/2022] [Accepted: 09/23/2022] [Indexed: 11/16/2022] Open
Abstract
Although several biclustering algorithms have been studied, few are used for cross-pattern identification across species using multi-omics data mining. A fast empirical Bayesian biclustering (Bi-EB) algorithm is developed to detect the patterns shared from both integrated omics data and between species. The Bi-EB algorithm addresses the clinical critical translational question using the bioinformatics strategy, which addresses how modules of genotype variation associated with phenotype from cancer cell screening data can be identified and how these findings can be directly translated to a cancer patient subpopulation. Empirical Bayesian probabilistic interpretation and ratio strategy are proposed in Bi-EB for the first time to detect the pairwise regulation patterns among species and variations in multiple omics on a gene level, such as proteins and mRNA. An expectation–maximization (EM) optimal algorithm is used to extract the foreground co-current variations out of its background noise data by adjusting parameters with bicluster membership probability threshold Ac; and the bicluster average probability p. Three simulation experiments and two real biology mRNA and protein data analyses conducted on the well-known Cancer Genomics Atlas (TCGA) and The Cancer Cell Line Encyclopedia (CCLE) verify that the proposed Bi-EB algorithm can significantly improve the clustering recovery and relevance accuracy, outperforming the other seven biclustering methods—Cheng and Church (CC), xMOTIFs, BiMax, Plaid, Spectral, FABIA, and QUBIC—with a recovery score of 0.98 and a relevance score of 0.99. At the same time, the Bi-EB algorithm is used to determine shared the causality patterns of mRNA to the protein between patients and cancer cells in TCGA and CCLE breast cancer. The clinically well-known treatment target protein module estrogen receptor (ER), ER (p118), AR, BCL2, cyclin E1, and IGFBP2 are identified in accordance with their mRNA expression variations in the luminal-like subtype. Ten genes, including CCNB1, CDH1, KDR, RAB25, PRKCA, etc., found which can maintain the high accordance of mRNA–protein for both breast cancer patients and cell lines in basal-like subtypes for the first time. Bi-EB provides a useful biclustering analysis tool to discover the cross patterns hidden both in multiple data matrixes (omics) and species. The implementation of the Bi-EB method in the clinical setting will have a direct impact on administrating translational research based on the cancer cell screening guidance.
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Ahmed R, Samanta S, Banerjee J, Kar SS, Dash SK. Modulatory role of miRNAs in thyroid and breast cancer progression and insights into their therapeutic manipulation. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2022; 3:100131. [PMID: 36568259 PMCID: PMC9780070 DOI: 10.1016/j.crphar.2022.100131] [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: 07/06/2022] [Revised: 08/22/2022] [Accepted: 09/25/2022] [Indexed: 11/07/2022] Open
Abstract
Over the past few decades, thyroid cancer has become one of the most common types of endocrine cancer, contributing to an increase in prevalence. In the year 2020, there were 586,202 newly diagnosed cases of thyroid cancer around the world. This constituted approximately 3.0% of all patients diagnosed with cancer. The World Health Organization reported that there will be 2.3 million women receiving treatment for breast cancer in 2020, with 685,000. Despite the fact that carcinoma is one of the world's leading causes of death, there is still a paucity of information about its biology. MicroRNAs (miRNAs; miRs) are non-coding RNAs that can reduce gene expression by cleaving the 3' untranslated regions of mRNA. These factors make them a potential protein translation inhibitor. Diverse biological mechanisms implicated in the genesis of cancer are modulated by miRNA. The investigation of global miRNA expression in cancer showed regulatory activity through up regulation and down-regulation in several cancers, including thyroid cancer and breast cancer. In thyroid cancer, miRNA influences several cancers related signaling pathways through modulating MAPK, PI3K, and the RAS pathway. In breast cancer, the regulatory activity of miRNA was played through the cyclin protein family, protein kinases and their inhibitors, and other growth promoters or suppressors, which modulated cell proliferation and cell cycle progression. This article's goal is to discuss key miRNA expressions that are involved in the development of thyroid and breast cancer as well as their therapeutic manipulation for these two specific cancer types.
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Affiliation(s)
- Rubai Ahmed
- Department of Physiology, University of Gour Banga, Malda, 732103, West Bengal, India
| | - Sovan Samanta
- Department of Physiology, University of Gour Banga, Malda, 732103, West Bengal, India
| | - Jhimli Banerjee
- Department of Physiology, University of Gour Banga, Malda, 732103, West Bengal, India
| | - Suvrendu Sankar Kar
- Department of Medicine, R.G.Kar Medical College and Hospital, Kolkata, 700004, West Bengal, India
| | - Sandeep Kumar Dash
- Department of Physiology, University of Gour Banga, Malda, 732103, West Bengal, India,Corresponding author.
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MET Oncogene Controls Invasive Growth by Coupling with NMDA Receptor. Cancers (Basel) 2022; 14:cancers14184408. [PMID: 36139568 PMCID: PMC9496780 DOI: 10.3390/cancers14184408] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/08/2022] [Accepted: 09/09/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary The MET oncogene, encoding the tyrosine kinase receptor for a hepatocyte growth factor (HGF), plays a key role in the onset and progression of aggressive forms of breast cancer. Recently, it was found that the glutamate receptor, which has a well-known role in the nervous system, is expressed in many types of tumors outside the nervous system and contributes to metastatic behavior in breast cancer cells. Here, we highlight that MET protein physically interacts with glutamate receptors in two highly metastatic breast cancer cell lines. HGF, which creates a supportive proinvasive microenvironment for the tumor cells, stabilizes this interaction. Pharmacological inhibition of glutamate receptors blunts the migration and invasion elicited by HGF, suggesting drug repurposing of glutamate receptor antagonists for anticancer therapy. Abstract The N-methyl-D-aspartate receptor (NMDAR) is a glutamate-gated ion channel involved in excitatory synaptic transmission. Outside the nervous system, the NMDAR is expressed in a variety of tissues and in cancers, notably in the highly invasive and metastatic triple-negative breast carcinoma. MET encodes the tyrosine kinase receptor for HGF and is a master regulator gene for “invasive growth”. In silico analysis shows that high expression of the NMDAR2B subunit is a negative prognostic factor in human invasive breast carcinoma. Here, we show that in triple-negative breast cancer cell lines NMDAR2B and MET proteins are coexpressed. HGF stimulation of these cells is followed by autophosphorylation of the MET kinase and phosphorylation of the NMDAR2B subunit at tyrosines 1252 and 1474. MET and phosphorylated NMDAR2B are physically associated, as demonstrated by co-immunoprecipitation, confocal immunofluorescence, and proximity ligation assays. Notably, pharmacological inhibition of NMDAR by MK801 and ifenprodil blunts the biological response to HGF. These results demonstrate the existence of a MET-NMDAR crosstalk driving the invasive program, paving the way for a new combinatorial therapy.
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Saitoh M. Epithelial–Mesenchymal Transition by Synergy between Transforming Growth Factor-β and Growth Factors in Cancer Progression. Diagnostics (Basel) 2022; 12:diagnostics12092127. [PMID: 36140527 PMCID: PMC9497767 DOI: 10.3390/diagnostics12092127] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/18/2022] [Accepted: 08/25/2022] [Indexed: 11/20/2022] Open
Abstract
Epithelial–mesenchymal transition (EMT) plays a crucial role in appropriate embryonic development, as well as wound healing, organ fibrosis, and cancer progression. During cancer progression, EMT is associated with the invasion, metastasis, and generation of circulating tumor cells and cancer stem cells, as well as resistance to chemo- and radiation therapy. EMT is induced by several transcription factors, known as EMT transcription factors (EMT-TFs). In nearly all cases, EMT-TFs appear to be regulated by growth factors or cytokines and extracellular matrix components. Among these factors, transforming growth factor (TGF)-β acts as the key mediator for EMT during physiological and pathological processes. TGF-β can initiate and maintain EMT by activating intracellular/intercellular signaling pathways and transcriptional factors. Recent studies have provided new insights into the molecular mechanisms underlying sustained EMT in aggressive cancer cells, EMT induced by TGF-β, and crosstalk between TGF-β and growth factors.
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Affiliation(s)
- Masao Saitoh
- Center for Medical Education and Sciences, Graduate School of Medicine, University of Yamanashi, 1110 Shimokato, Chuo-City, Yamanashi 409-3898, Japan
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Sato F, Sagara A, Tajima K, Miura S, Inaba K, Ando Y, Oku T, Murakami T, Kato Y, Yumoto T. COL8A1 facilitates the growth of triple-negative breast cancer via FAK/Src activation. Breast Cancer Res Treat 2022; 194:243-256. [PMID: 35624176 DOI: 10.1007/s10549-022-06635-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 04/18/2022] [Indexed: 11/29/2022]
Abstract
PURPOSE Triple-negative breast cancer (TNBC) is one of the most aggressive breast cancer subtypes, and treatment options are limited because of the lack of signature molecules and heterogeneous properties of cancer. COL8A1 expression is higher in breast cancer than in normal tissues and is strongly correlated with worse overall survival in patients with breast cancer. However, the biological function of COL8A1 on cancer progression is not fully understood. In this study, we investigated the biological function of COL8A1 on TNBC progression. METHODS COL8A1-deficient cells were generated using the CRISPR-Cas9 system. The tumor growth and metastasis of TNBC cells were evaluated using three-dimensional culture (3D) methods and xenograft mouse models. The activation of focal adhesion kinase (FAK)/Src by COL8A1 in TNBC cells was evaluated by immunoblotting. RESULTS COL8A1 expression was primarily distributed into TNBC cell lines. Further, relapse-free survival in TNBC patients with the MSL subtype was strongly associated with the COL8A1 expression. MDA-MB-231 and Hs578T cells, classified as the MSL subtype, strongly express COL8A1, and COL8A1 protein expression was induced by hypoxia in both cell lines. Loss of COL8A1 expression inhibited spheroid /tumor growth and metastasis in vitro and in vivo. Further, exogenous COL8A1 promoted TNBC growth via the FAK/Src activation. Finally, the spheroid growth of MDA-MB-231 and Hs578T cells was inhibited by defactinib, a FAK inhibitor, without cytotoxicity. CONCLUSION These results indicate that COL8A1-mediated FAK/Src activation produces a more aggressive phenotype in TNBC, and its target inhibition may be an efficacious treatment for TNBC.
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Affiliation(s)
- Fumiaki Sato
- Laboratory of Analytical Pathophysiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
| | - Atsunobu Sagara
- Laboratory of Analytical Pathophysiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Kaede Tajima
- Laboratory of Analytical Pathophysiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Shotaro Miura
- Laboratory of Analytical Pathophysiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Kenjiro Inaba
- Laboratory of Analytical Pathophysiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Yusuke Ando
- Laboratory of Clinical Pathology, Faculty of Pharmacy, Josai University, 1-1, Keyaki-dai, Sakado City, Saitama, 350-0295, Japan
| | - Teruaki Oku
- Department of Microbiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Takashi Murakami
- Department of Microbiology, Faculty of Medicine, Saitama Medical University, 38 Moro-Hongo, Moroyama, Iruma, Saitama, 350-0495, Japan
| | - Yoshinori Kato
- Laboratory of Biopharmaceutics and Analytical Science, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Tetsuro Yumoto
- Laboratory of Analytical Pathophysiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
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Li ZD, Yu X, Mei Z, Zeng T, Chen L, Xu XL, Li H, Huang T, Cai YD. Identifying luminal and basal mammary cell specific genes and their expression patterns during pregnancy. PLoS One 2022; 17:e0267211. [PMID: 35486595 PMCID: PMC9053804 DOI: 10.1371/journal.pone.0267211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 04/05/2022] [Indexed: 11/25/2022] Open
Abstract
Mammary gland is present in all mammals and usually functions in producing milk to feed the young offspring. Mammogenesis refers to the growth and development of mammary gland, which begins at puberty and ends after lactation. Pregnancy is regulated by various cytokines, which further contributes to mammary gland development. Epithelial cells, including basal and luminal cells, are one of the major components of mammary gland cells. The development of basal and luminal cells has been observed to significantly differ at different stages. However, the underlying mechanisms for differences between basal and luminal cells have not been fully studied. To explore the mechanisms underlying the differentiation of mammary progenitors or their offspring into luminal and myoepithelial cells, the single-cell sequencing data on mammary epithelia cells of virgin and pregnant mouse was deeply investigated in this work. We evaluated features by using Monte Carlo feature selection and plotted the incremental feature selection curve with support vector machine or RIPPER to find the optimal gene features and rules that can divide epithelial cells into four clusters with different cell subtypes like basal and luminal cells and different phases like pregnancy and virginity. As representations, the feature genes Cldn7, Gjb6, Sparc, Cldn3, Cited1, Krt17, Spp1, Cldn4, Gjb2 and Cldn19 might play an important role in classifying the epithelial mammary cells. Notably, seven most important rules based on the combination of cell-specific and tissue-specific expressions of feature genes effectively classify the epithelial mammary cells in a quantitative and interpretable manner.
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Affiliation(s)
- Zhan Dong Li
- College of Biological and Food Engineering, Jilin Engineering Normal University, Changchun, China
| | - Xiangtian Yu
- Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Zi Mei
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Tao Zeng
- Bio-Med Big Data Center, CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Lei Chen
- College of Information Engineering, Shanghai Maritime University, Shanghai, China
| | - Xian Ling Xu
- Guangdong AIB Polytechnic College, Guangzhou, China
| | - Hao Li
- College of Biological and Food Engineering, Jilin Engineering Normal University, Changchun, China
| | - Tao Huang
- Bio-Med Big Data Center, CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
- * E-mail: (TH); (YDC)
| | - Yu-Dong Cai
- School of Life Sciences, Shanghai University, Shanghai, China
- * E-mail: (TH); (YDC)
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Li Z, McGinn O, Wu Y, Bahreini A, Priedigkeit NM, Ding K, Onkar S, Lampenfeld C, Sartorius CA, Miller L, Rosenzweig M, Cohen O, Wagle N, Richer JK, Muller WJ, Buluwela L, Ali S, Bruno TC, Vignali DAA, Fang Y, Zhu L, Tseng GC, Gertz J, Atkinson JM, Lee AV, Oesterreich S. ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation. Nat Commun 2022; 13:2011. [PMID: 35440136 PMCID: PMC9019037 DOI: 10.1038/s41467-022-29498-9] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 03/15/2022] [Indexed: 12/26/2022] Open
Abstract
Estrogen receptor alpha (ER/ESR1) is frequently mutated in endocrine resistant ER-positive (ER+) breast cancer and linked to ligand-independent growth and metastasis. Despite the distinct clinical features of ESR1 mutations, their role in intrinsic subtype switching remains largely unknown. Here we find that ESR1 mutant cells and clinical samples show a significant enrichment of basal subtype markers, and six basal cytokeratins (BCKs) are the most enriched genes. Induction of BCKs is independent of ER binding and instead associated with chromatin reprogramming centered around a progesterone receptor-orchestrated insulated neighborhood. BCK-high ER+ primary breast tumors exhibit a number of enriched immune pathways, shared with ESR1 mutant tumors. S100A8 and S100A9 are among the most induced immune mediators and involve in tumor-stroma paracrine crosstalk inferred by single-cell RNA-seq from metastatic tumors. Collectively, these observations demonstrate that ESR1 mutant tumors gain basal features associated with increased immune activation, encouraging additional studies of immune therapeutic vulnerabilities.
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Affiliation(s)
- Zheqi Li
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
- Womens Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Magee-Womens Research Institute, Pittsburgh, PA, USA
| | - Olivia McGinn
- Womens Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Magee-Womens Research Institute, Pittsburgh, PA, USA
| | - Yang Wu
- Womens Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Magee-Womens Research Institute, Pittsburgh, PA, USA
- School of Medicine, Tsinghua University, Beijing, China
| | - Amir Bahreini
- Womens Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Magee-Womens Research Institute, Pittsburgh, PA, USA
- Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Nolan M Priedigkeit
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
- Womens Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Magee-Womens Research Institute, Pittsburgh, PA, USA
| | - Kai Ding
- Womens Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Magee-Womens Research Institute, Pittsburgh, PA, USA
| | - Sayali Onkar
- Womens Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Magee-Womens Research Institute, Pittsburgh, PA, USA
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
- Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Caleb Lampenfeld
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
- Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Carol A Sartorius
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Lori Miller
- Womens Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Magee-Womens Research Institute, Pittsburgh, PA, USA
| | | | - Ofir Cohen
- Department of Medical Oncology and Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Nikhil Wagle
- Department of Medical Oncology and Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Jennifer K Richer
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - William J Muller
- Goodman Cancer Centre and Departments of Biochemistry and Medicine, McGill University, Montreal, QC, Canada
| | - Laki Buluwela
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK
| | - Simak Ali
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK
| | - Tullia C Bruno
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
- Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Dario A A Vignali
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
- Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Yusi Fang
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Li Zhu
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA
| | - George C Tseng
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jason Gertz
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - Jennifer M Atkinson
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
- Womens Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Magee-Womens Research Institute, Pittsburgh, PA, USA
| | - Adrian V Lee
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
- Womens Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Magee-Womens Research Institute, Pittsburgh, PA, USA
- Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Steffi Oesterreich
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
- Womens Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
- Magee-Womens Research Institute, Pittsburgh, PA, USA.
- Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
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Han H, Wang Y, Curto J, Gurrapu S, Laudato S, Rumandla A, Chakraborty G, Wang X, Chen H, Jiang Y, Kumar D, Caggiano EG, Capogiri M, Zhang B, Ji Y, Maity SN, Hu M, Bai S, Aparicio AM, Efstathiou E, Logothetis CJ, Navin N, Navone NM, Chen Y, Giancotti FG. Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis. Cell Rep 2022; 39:110595. [PMID: 35385726 PMCID: PMC9414743 DOI: 10.1016/j.celrep.2022.110595] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 09/18/2021] [Accepted: 03/09/2022] [Indexed: 12/13/2022] Open
Abstract
Bioinformatic analysis of 94 patient-derived xenografts (PDXs), cell lines, and organoids (PCOs) identifies three intrinsic transcriptional subtypes of metastatic castration-resistant prostate cancer: androgen receptor (AR) pathway + prostate cancer (PC) (ARPC), mesenchymal and stem-like PC (MSPC), and neuroendocrine PC (NEPC). A sizable proportion of castration-resistant and metastatic stage PC (M-CRPC) cases are admixtures of ARPC and MSPC. Analysis of clinical datasets and mechanistic studies indicates that MSPC arises from ARPC as a consequence of therapy-induced lineage plasticity. AR blockade with enzalutamide induces (1) transcriptional silencing of TP53 and hence dedifferentiation to a hybrid epithelial and mesenchymal and stem-like state and (2) inhibition of BMP signaling, which promotes resistance to AR inhibition. Enzalutamide-tolerant LNCaP cells re-enter the cell cycle in response to neuregulin and generate metastasis in mice. Combined inhibition of HER2/3 and AR or mTORC1 exhibits efficacy in models of ARPC and MSPC or MSPC, respectively. These results define MSPC, trace its origin to therapy-induced lineage plasticity, and reveal its sensitivity to HER2/3 inhibition.
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Affiliation(s)
- Hyunho Han
- Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA; Department of Urology, Urological Science Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Yan Wang
- Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA; Herbert Irving Comprehensive Cancer Center and Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Josue Curto
- Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA; Herbert Irving Comprehensive Cancer Center and Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Sreeharsha Gurrapu
- Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA; Herbert Irving Comprehensive Cancer Center and Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Sara Laudato
- Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA
| | - Alekya Rumandla
- Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA; UT MDACC UT Health Graduate School of Biomedical Sciences, Houston, TX 77030, USA
| | | | - Xiaobo Wang
- Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA; Herbert Irving Comprehensive Cancer Center and Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; UT MDACC UT Health Graduate School of Biomedical Sciences, Houston, TX 77030, USA
| | - Hong Chen
- Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA
| | - Yan Jiang
- Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA
| | - Dhiraj Kumar
- Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA; Herbert Irving Comprehensive Cancer Center and Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Emily G Caggiano
- Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA; UT MDACC UT Health Graduate School of Biomedical Sciences, Houston, TX 77030, USA
| | - Monica Capogiri
- Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA
| | - Boyu Zhang
- Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA
| | - Yan Ji
- Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA
| | - Sankar N Maity
- Department of GU Oncology, UT MDACC, Houston, TX 77054, USA
| | - Min Hu
- Department of Genetics, UT MDACC, Houston, TX 77054, USA
| | - Shanshan Bai
- Department of Genetics, UT MDACC, Houston, TX 77054, USA
| | - Ana M Aparicio
- Department of GU Oncology, UT MDACC, Houston, TX 77054, USA
| | | | | | - Nicholas Navin
- Department of Genetics, UT MDACC, Houston, TX 77054, USA
| | - Nora M Navone
- Department of GU Oncology, UT MDACC, Houston, TX 77054, USA
| | - Yu Chen
- Human Oncology and Pathogenesis Program and Department of Medicine, MSKCC, New York, NY 10065, USA
| | - Filippo G Giancotti
- Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA; Herbert Irving Comprehensive Cancer Center and Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
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Ertl IE, Lemberger U, Ilijazi D, Hassler MR, Bruchbacher A, Brettner R, Kronabitter H, Gutmann M, Vician P, Zeitler G, Koren A, Lardeau CH, Mohr T, Haitel A, Compérat E, Oszwald A, Wasinger G, Clozel T, Elemento O, Kubicek S, Berger W, Shariat SF. Molecular and Pharmacological Bladder Cancer Therapy Screening: Discovery of Clofarabine as a Highly Active Compound. Eur Urol 2022; 82:261-270. [PMID: 35393162 DOI: 10.1016/j.eururo.2022.03.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 02/20/2022] [Accepted: 03/10/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND The heterogeneity of bladder cancers (BCs) is a major challenge for the development of novel therapies. However, given the high rates of recurrence and/or treatment failure, the identification of effective therapeutic strategies is an urgent clinical need. OBJECTIVE We aimed to establish a model system for drug identification/repurposing in order to identify novel therapies for the treatment of BC. DESIGN, SETTING, AND PARTICIPANTS A collection of commercially available BC cell lines (n = 32) was comprehensively characterized. A panel of 23 cell lines, representing a broad spectrum of BC, was selected to perform a high-throughput drug screen. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Positive hits were defined as compounds giving >50% inhibition in at least one BC cell line. RESULTS AND LIMITATIONS Amongst >1700 tested chemical compounds, a total of 471 substances exhibited antineoplastic effects. Clofarabine, an antimetabolite drug used as third-line treatment for childhood acute lymphoblastic leukaemia, was amongst the limited number of drugs with inhibitory effects on cell lines of all intrinsic subtypes. We, thus, reassessed the substance and confirmed its inhibitory effects on commercially available cell lines and patient-derived cell cultures representing various disease stages, intrinsic subtypes, and histologic variants. To verify these effects in vivo, a patient-derived cell xenograft model for urothelial carcinoma (UC) was used. Well-tolerated doses of clofarabine induced complete remission in all treated animals (n = 12) suffering from both early- and late-stage disease. We further took advantage of another patient-derived cell xenograft model originating from the rare disease entity sarcomatoid carcinoma (SaC). Similarly to UC xenograft mice, clofarabine induced subcomplete to complete tumour remissions in all treated animals (n = 8). CONCLUSIONS The potent effects of clofarabine in vitro and in vivo suggest that our findings may be of high clinical relevance. Clinical trials are needed to assess the value of clofarabine in improving BC patient care. PATIENT SUMMARY We used commercially available cell lines for the identification of novel drugs for the treatment of bladder cancer. We confirmed the effects of one of these drugs, clofarabine, in patient-derived cell lines and two different mouse models, thereby demonstrating a potential clinical relevance of this substance in bladder cancer treatment.
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Affiliation(s)
- Iris E Ertl
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Ursula Lemberger
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Dafina Ilijazi
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Melanie R Hassler
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Andreas Bruchbacher
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Robert Brettner
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Hannah Kronabitter
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Michael Gutmann
- Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria
| | - Petra Vician
- Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria
| | - Gerhard Zeitler
- Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria
| | - Anna Koren
- CeMM Research Center for Molecular Medicine, Vienna, Austria
| | | | - Thomas Mohr
- Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria
| | - Andrea Haitel
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Eva Compérat
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - André Oszwald
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Gabriel Wasinger
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Thomas Clozel
- OWKIN, New York City, NY, USA; Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, NY, USA
| | - Olivier Elemento
- Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA; Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, NY, USA; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Stefan Kubicek
- CeMM Research Center for Molecular Medicine, Vienna, Austria
| | - Walter Berger
- Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.
| | - Shahrokh F Shariat
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, Weill Cornell Medical College, New York, NY, USA; Department of Urology, University of Texas Southwestern, Dallas, TX, USA; Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; Hourani Center for Applied Scientific Research, Al-Ahliyya Amman University, Amman, Jordan
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Jones GS, Hoadley KA, Benefield H, Olsson LT, Hamilton AM, Bhattacharya A, Kirk EL, Tipaldos HJ, Fleming JM, Williams KP, Love MI, Nichols HB, Olshan AF, Troester MA. Racial differences in breast cancer outcomes by hepatocyte growth factor pathway expression. Breast Cancer Res Treat 2022; 192:447-455. [PMID: 35034243 PMCID: PMC9380654 DOI: 10.1007/s10549-021-06497-w] [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: 10/28/2021] [Accepted: 12/16/2021] [Indexed: 11/02/2022]
Abstract
PURPOSE Black women have a 40% increased risk of breast cancer-related mortality. These outcome disparities may reflect differences in tumor pathways and a lack of targetable therapies for specific subtypes that are more common in Black women. Hepatocyte growth factor (HGF) is a targetable pathway that promotes breast cancer tumorigenesis, is associated with basal-like breast cancer, and is differentially expressed by race. This study assessed whether a 38-gene HGF expression signature is associated with recurrence and survival in Black and non-Black women. METHODS Study participants included 1957 invasive breast cancer cases from the Carolina Breast Cancer Study. The HGF signature was evaluated in association with recurrence (n = 1251, 171 recurrences), overall, and breast cancer-specific mortality (n = 706, 190/328 breast cancer/overall deaths) using Cox proportional hazard models. RESULTS Women with HGF-positive tumors had higher recurrence rates [HR 1.88, 95% CI (1.19, 2.98)], breast cancer-specific mortality [HR 1.90, 95% CI (1.26, 2.85)], and overall mortality [HR 1.69; 95% CI (1.17, 2.43)]. Among Black women, HGF positivity was significantly associated with higher 5-year rate of recurrence [HR 1.73; 95% CI (1.01, 2.99)], but this association was not significant in non-Black women [HR 1.68; 95% CI (0.72, 3.90)]. Among Black women, HGF-positive tumors had elevated breast cancer-specific mortality [HR 1.80, 95% CI (1.05, 3.09)], which was not significant in non-Black women [HR 1.52; 95% CI (0.78, 2.99)]. CONCLUSION This multi-gene HGF signature is a poor-prognosis feature for breast cancer and may identify patients who could benefit from HGF-targeted treatments, an unmet need for Black and triple-negative patients.
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Affiliation(s)
- Gieira S Jones
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina-Chapel Hill, 253 Rosenau Hall, CB #7435, 135 Dauer Drive, Chapel Hill, NC, 27599-7400, USA
| | - Katherine A Hoadley
- Department of Genetics, University of North Carolina-Chapel Hill-Chapel Hill, Chapel Hill, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, USA
| | - Halei Benefield
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina-Chapel Hill, 253 Rosenau Hall, CB #7435, 135 Dauer Drive, Chapel Hill, NC, 27599-7400, USA
| | - Linnea T Olsson
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina-Chapel Hill, 253 Rosenau Hall, CB #7435, 135 Dauer Drive, Chapel Hill, NC, 27599-7400, USA
| | - Alina M Hamilton
- Department of Pathology and Laboratory Medicine, University of North Carolina-Chapel Hill, Chapel Hill, USA
| | - Arjun Bhattacharya
- Department of Biostatistics, University of North Carolina-Chapel Hill, Chapel Hill, USA
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, USA
- Institute for Quantitative and Computational Biosciences, David Geffen School of Medicine, University of California, Los Angeles, USA
| | - Erin L Kirk
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina-Chapel Hill, 253 Rosenau Hall, CB #7435, 135 Dauer Drive, Chapel Hill, NC, 27599-7400, USA
| | - Heather J Tipaldos
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, USA
| | - Jodie M Fleming
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, USA
- Department of Biological and Biomedical Sciences, North Carolina Central University, Durham, USA
| | - Kevin P Williams
- Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, USA
- Department of Pharmaceutical Sciences, North Carolina Central University, Durham, USA
| | - Michael I Love
- Department of Genetics, University of North Carolina-Chapel Hill-Chapel Hill, Chapel Hill, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, USA
- Department of Biostatistics, University of North Carolina-Chapel Hill, Chapel Hill, USA
| | - Hazel B Nichols
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina-Chapel Hill, 253 Rosenau Hall, CB #7435, 135 Dauer Drive, Chapel Hill, NC, 27599-7400, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, USA
| | - Andrew F Olshan
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina-Chapel Hill, 253 Rosenau Hall, CB #7435, 135 Dauer Drive, Chapel Hill, NC, 27599-7400, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, USA
| | - Melissa A Troester
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina-Chapel Hill, 253 Rosenau Hall, CB #7435, 135 Dauer Drive, Chapel Hill, NC, 27599-7400, USA.
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, USA.
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Dunn J, McCuaig RD, Tan AHY, Tu WJ, Wu F, Wagstaff KM, Zafar A, Ali S, Diwakar H, Dahlstrom JE, Bean EG, Forwood JK, Tsimbalyuk S, Cross EM, Hardy K, Bain AL, Ahern E, Dolcetti R, Mazzieri R, Yip D, Eastgate M, Malik L, Milburn P, Jans DA, Rao S. Selective Targeting of Protein Kinase C (PKC)-θ Nuclear Translocation Reduces Mesenchymal Gene Signatures and Reinvigorates Dysfunctional CD8 + T Cells in Immunotherapy-Resistant and Metastatic Cancers. Cancers (Basel) 2022; 14:1596. [PMID: 35326747 PMCID: PMC8946217 DOI: 10.3390/cancers14061596] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/07/2022] [Accepted: 03/14/2022] [Indexed: 02/05/2023] Open
Abstract
Protein kinase C (PKC)-θ is a serine/threonine kinase with both cytoplasmic and nuclear functions. Nuclear chromatin-associated PKC-θ (nPKC-θ) is increasingly recognized to be pathogenic in cancer, whereas its cytoplasmic signaling is restricted to normal T-cell function. Here we show that nPKC-θ is enriched in circulating tumor cells (CTCs) in patients with triple-negative breast cancer (TNBC) brain metastases and immunotherapy-resistant metastatic melanoma and is associated with poor survival in immunotherapy-resistant disease. To target nPKC-θ, we designed a novel PKC-θ peptide inhibitor (nPKC-θi2) that selectively inhibits nPKC-θ nuclear translocation but not PKC-θ signaling in healthy T cells. Targeting nPKC-θ reduced mesenchymal cancer stem cell signatures in immunotherapy-resistant CTCs and TNBC xenografts. PKC-θ was also enriched in the nuclei of CD8+ T cells isolated from stage IV immunotherapy-resistant metastatic cancer patients. We show for the first time that nPKC-θ complexes with ZEB1, a key repressive transcription factor in epithelial-to-mesenchymal transition (EMT), in immunotherapy-resistant dysfunctional PD1+/CD8+ T cells. nPKC-θi2 inhibited the ZEB1/PKC-θ repressive complex to induce cytokine production in CD8+ T cells isolated from patients with immunotherapy-resistant disease. These data establish for the first time that nPKC-θ mediates immunotherapy resistance via its activity in CTCs and dysfunctional CD8+ T cells. Disrupting nPKC-θ but retaining its cytoplasmic function may offer a means to target metastases in combination with chemotherapy or immunotherapy.
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Affiliation(s)
- Jenny Dunn
- Gene Regulation and Translational Medicine Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; (J.D.); (R.D.M.); (W.J.T.); (A.L.B.)
- Melanie Swan Memorial Translational Centre, Faculty of Science and Technology, University of Canberra, Canberra, ACT 2617, Australia; (A.H.Y.T.); (F.W.); (A.Z.); (K.H.)
| | - Robert D. McCuaig
- Gene Regulation and Translational Medicine Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; (J.D.); (R.D.M.); (W.J.T.); (A.L.B.)
- Melanie Swan Memorial Translational Centre, Faculty of Science and Technology, University of Canberra, Canberra, ACT 2617, Australia; (A.H.Y.T.); (F.W.); (A.Z.); (K.H.)
| | - Abel H. Y. Tan
- Melanie Swan Memorial Translational Centre, Faculty of Science and Technology, University of Canberra, Canberra, ACT 2617, Australia; (A.H.Y.T.); (F.W.); (A.Z.); (K.H.)
| | - Wen Juan Tu
- Gene Regulation and Translational Medicine Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; (J.D.); (R.D.M.); (W.J.T.); (A.L.B.)
- Melanie Swan Memorial Translational Centre, Faculty of Science and Technology, University of Canberra, Canberra, ACT 2617, Australia; (A.H.Y.T.); (F.W.); (A.Z.); (K.H.)
| | - Fan Wu
- Melanie Swan Memorial Translational Centre, Faculty of Science and Technology, University of Canberra, Canberra, ACT 2617, Australia; (A.H.Y.T.); (F.W.); (A.Z.); (K.H.)
| | - Kylie M. Wagstaff
- Cancer Targeting and Nuclear Therapeutics Lab, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia;
| | - Anjum Zafar
- Melanie Swan Memorial Translational Centre, Faculty of Science and Technology, University of Canberra, Canberra, ACT 2617, Australia; (A.H.Y.T.); (F.W.); (A.Z.); (K.H.)
| | - Sayed Ali
- Medical Oncology, St John of God Midland Public and Private Hospitals, Perth, WA 6056, Australia;
| | - Himanshu Diwakar
- Woden Specialist Medical Centre, I-MED Radiology Network, Canberra, ACT 2606, Australia;
| | - Jane E. Dahlstrom
- Anatomical Pathology, ACT Pathology, The Canberra Hospital, Canberra Health Services, Canberra, ACT 2605, Australia; (J.E.D.); (E.G.B.)
- ANU Medical School, College of Health and Medicine, The Australian National University, Canberra, ACT 0200, Australia; (D.Y.); (L.M.)
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 0200, Australia;
| | - Elaine G. Bean
- Anatomical Pathology, ACT Pathology, The Canberra Hospital, Canberra Health Services, Canberra, ACT 2605, Australia; (J.E.D.); (E.G.B.)
| | - Jade K. Forwood
- School of Dentistry and Medical Sciences, Charles Sturt University, Wagga Wagga, NSW 2678, Australia; (J.K.F.); (S.T.); (E.M.C.)
| | - Sofiya Tsimbalyuk
- School of Dentistry and Medical Sciences, Charles Sturt University, Wagga Wagga, NSW 2678, Australia; (J.K.F.); (S.T.); (E.M.C.)
| | - Emily M. Cross
- School of Dentistry and Medical Sciences, Charles Sturt University, Wagga Wagga, NSW 2678, Australia; (J.K.F.); (S.T.); (E.M.C.)
| | - Kristine Hardy
- Melanie Swan Memorial Translational Centre, Faculty of Science and Technology, University of Canberra, Canberra, ACT 2617, Australia; (A.H.Y.T.); (F.W.); (A.Z.); (K.H.)
| | - Amanda L. Bain
- Gene Regulation and Translational Medicine Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; (J.D.); (R.D.M.); (W.J.T.); (A.L.B.)
| | - Elizabeth Ahern
- Department of Medical Oncology, Monash Health and Monash University, Melbourne, VIC 3168, Australia;
- Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia
| | - Riccardo Dolcetti
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; (R.D.); (R.M.)
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia
- Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC 3010, Australia
- The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD 4102, Australia
| | - Roberta Mazzieri
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; (R.D.); (R.M.)
- The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD 4102, Australia
| | - Desmond Yip
- ANU Medical School, College of Health and Medicine, The Australian National University, Canberra, ACT 0200, Australia; (D.Y.); (L.M.)
- Department of Medical Oncology, Canberra Health Services, The Canberra Hospital, Canberra, ACT 2605, Australia
| | - Melissa Eastgate
- Department of Medical Oncology, Royal Brisbane and Women’s Hospital, Brisbane, QLD 4029, Australia;
- Faculty of Medicine, University of Queensland, Herston, QLD 4006, Australia
| | - Laeeq Malik
- ANU Medical School, College of Health and Medicine, The Australian National University, Canberra, ACT 0200, Australia; (D.Y.); (L.M.)
- Department of Medical Oncology, Canberra Health Services, The Canberra Hospital, Canberra, ACT 2605, Australia
| | - Peter Milburn
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 0200, Australia;
| | - David A. Jans
- Nuclear Signaling Lab, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia;
| | - Sudha Rao
- Gene Regulation and Translational Medicine Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; (J.D.); (R.D.M.); (W.J.T.); (A.L.B.)
- Melanie Swan Memorial Translational Centre, Faculty of Science and Technology, University of Canberra, Canberra, ACT 2617, Australia; (A.H.Y.T.); (F.W.); (A.Z.); (K.H.)
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Glycosphingolipids in human embryonic stem cells and breast cancer stem cells, and potential cancer therapy strategies based on their structures and functions. Glycoconj J 2022; 39:177-195. [PMID: 35267131 DOI: 10.1007/s10719-021-10032-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 11/27/2021] [Accepted: 12/08/2021] [Indexed: 12/26/2022]
Abstract
Expression profiles of glycosphingolipids (GSLs) in human embryonic stem cell (hESC) lines and their differentiated embryoid body (EB) outgrowth cells, consisting of three germ layers, were surveyed systematically. Several globo- and lacto-series GSLs were identified in undifferentiated hESCs and during differentiation of hESCs to EB outgrowth cells, and core structure switching of these GSLs to gangliosides was observed. Such switching was attributable to altered expression of key glycosyltransferases (GTs) in GSL biosynthetic pathways, reflecting the unique stage-specific transitions and mechanisms characteristic of the differentiation process. Lineage-specific differentiation of hESCs was associated with further GSL alterations. During differentiation of undifferentiated hESCs to neural progenitor cells, core structure switching from globo- and lacto-series to primarily gangliosides (particularly GD3) was again observed. During differentiation to endodermal cells, alterations of GSL profiles were distinct from those in differentiation to EB outgrowth or neural progenitor cells, with high expression of Gb4Cer and low expression of stage-specific embryonic antigen (SSEA)-3, -4, or GD3 in endodermal cells. Again, such profile changes resulted from alterations of key GTs in GSL biosynthetic pathways. Novel glycan structures identified on hESCs and their differentiated counterparts presumably play functional roles in hESCs and related cancer or cancer stem cells, and will be useful as surface biomarkers. We also examined GSL expression profiles in breast cancer stem cells (CSCs), using a model of epithelial-mesenchymal transition (EMT)-induced human breast CSCs. We found that GD2 and GD3, together with their common upstream GTs, GD3 synthase (GD3S) and GD2/GM2 synthase, maintained stem cell phenotype in breast CSCs. Subsequent studies showed that GD3 was associated with epidermal growth factor receptor (EGFR), and activated EGFR signaling in breast CSCs and breast cancer cell lines. GD3S knockdown enhanced cytotoxicity of gefitinib (an EGFR kinase inhibitor) in resistant MDA-MB468 cells, both in vitro and in vivo. Our findings indicate that GD3S contributes to gefitinib resistance in EGFR-positive breast cancer cells, and is a potentially useful therapeutic target in drug-resistant breast cancers.
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46
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Valle F, Osella M, Caselle M. Multiomics Topic Modeling for Breast Cancer Classification. Cancers (Basel) 2022; 14:1150. [PMID: 35267458 PMCID: PMC8909787 DOI: 10.3390/cancers14051150] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 02/18/2022] [Indexed: 12/04/2022] Open
Abstract
The integration of transcriptional data with other layers of information, such as the post-transcriptional regulation mediated by microRNAs, can be crucial to identify the driver genes and the subtypes of complex and heterogeneous diseases such as cancer. This paper presents an approach based on topic modeling to accomplish this integration task. More specifically, we show how an algorithm based on a hierarchical version of stochastic block modeling can be naturally extended to integrate any combination of 'omics data. We test this approach on breast cancer samples from the TCGA database, integrating data on messenger RNA, microRNAs, and copy number variations. We show that the inclusion of the microRNA layer significantly improves the accuracy of subtype classification. Moreover, some of the hidden structures or "topics" that the algorithm extracts actually correspond to genes and microRNAs involved in breast cancer development and are associated to the survival probability.
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Affiliation(s)
- Filippo Valle
- Physics Department, University of Turin and INFN, via P. Giuria 1, 10125 Turin, Italy; (M.O.); (M.C.)
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Subhan MA. Advances with metal oxide-based nanoparticles as MDR metastatic breast cancer therapeutics and diagnostics. RSC Adv 2022; 12:32956-32978. [PMID: 36425155 PMCID: PMC9670683 DOI: 10.1039/d2ra02005j] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 11/08/2022] [Indexed: 11/18/2022] Open
Abstract
Metal oxide nanoparticles have attracted increased attention due to their emerging applications in cancer detection and therapy. This study envisioned to highlight the great potential of metal oxide NPs due to their interesting properties including high payload, response to magnetic field, affluence of surface modification to overcome biological barriers, and biocompatibility. Mammogram, ultrasound, X-ray computed tomography (CT), MRI, positron emission tomography (PET), optical or fluorescence imaging are used for breast imaging. Drug-loaded metal oxide nanoparticle delivered to the breast cancer cells leads to higher drug uptake. Thus, enhanced the cytotoxicity to target cells compared to free drug. The drug loaded metal oxide nanoparticle formulations hold great promise to enhance efficacy of breast cancer therapy including multidrug resistant (MDR) and metastatic breast cancers. Various metal oxides including magnetic metal oxides and magnetosomes are of current interests to explore cancer drug delivery and diagnostic efficacy especially for metastatic breast cancer. Metal oxide-based nanocarrier formulations are promising for their usage in drug delivery and release to breast cancer cells, cancer diagnosis and their clinical translations. Biomarker targeted therapy approaches for TNBC using metal oxide-based NPs are highly effective and promising.![]()
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Affiliation(s)
- Md Abdus Subhan
- Department of Chemistry, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh
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48
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Menck K, Heinrichs S, Wlochowitz D, Sitte M, Noeding H, Janshoff A, Treiber H, Ruhwedel T, Schatlo B, von der Brelie C, Wiemann S, Pukrop T, Beißbarth T, Binder C, Bleckmann A. WNT11/ROR2 signaling is associated with tumor invasion and poor survival in breast cancer. J Exp Clin Cancer Res 2021; 40:395. [PMID: 34911552 PMCID: PMC8672621 DOI: 10.1186/s13046-021-02187-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 11/16/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Breast cancer has been associated with activation of the WNT signaling pathway, although no driver mutations in WNT genes have been found yet. Instead, a high expression of the alternative WNT receptor ROR2 was observed, in particular in breast cancer brain metastases. However, its respective ligand and downstream signaling in this context remained unknown. METHODS We modulated the expression of ROR2 in human breast cancer cells and characterized their gene and protein expression by RNA-Seq, qRT-PCR, immunoblots and reverse phase protein array (RPPA) combined with network analyses to understand the molecular basis of ROR2 signaling in breast cancer. Using co-immunoprecipitations, we verified the interaction of ROR2 with the identified ligand, WNT11. The functional consequences of WNT11/ROR2 signaling for tumor cell aggressiveness were assessed by microscopy, impedance sensing as well as viability and invasion assays. To evaluate the translational significance of our findings, we performed gene set enrichment, expression and survival analyses on human breast cancer brain metastases. RESULTS We found ROR2 to be highly expressed in aggressive breast tumors and associated with worse metastasis-free survival. ROR2 overexpression induced a BRCAness-like phenotype in a cell-context specific manner and rendered cells resistant to PARP inhibition. High levels of ROR2 were furthermore associated with defects in cell morphology and cell-cell-contacts leading to increased tumor invasiveness. On a molecular level, ROR2 overexpression upregulated several non-canonical WNT ligands, in particular WNT11. Co-immunoprecipitation confirmed that WNT11 indeed interacts with the cysteine-rich domain of ROR2 and triggers its invasion-promoting signaling via RHO/ROCK. Knockdown of WNT11 reversed the pro-invasive phenotype and the cellular changes in ROR2-overexpressing cells. CONCLUSIONS Taken together, our study revealed a novel auto-stimulatory loop in which ROR2 triggers the expression of its own ligand, WNT11, resulting in enhanced tumor invasion associated with breast cancer metastasis.
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Affiliation(s)
- Kerstin Menck
- Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, 48149, Münster, Germany
- West German Cancer Center, University Hospital Münster, 48149, Münster, Germany
- Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany
| | - Saskia Heinrichs
- Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, 48149, Münster, Germany
- West German Cancer Center, University Hospital Münster, 48149, Münster, Germany
- Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany
| | - Darius Wlochowitz
- Department of Medical Bioinformatics, University Medical Center Göttingen, 37099, Göttingen, Germany
| | - Maren Sitte
- Department of Medical Bioinformatics, University Medical Center Göttingen, 37099, Göttingen, Germany
| | - Helen Noeding
- Institute for Physical Chemistry, Georg August University Göttingen, 37075, Göttingen, Germany
| | - Andreas Janshoff
- Institute for Physical Chemistry, Georg August University Göttingen, 37075, Göttingen, Germany
| | - Hannes Treiber
- Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany
- Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075, Göttingen, Germany
| | - Torben Ruhwedel
- Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075, Göttingen, Germany
| | - Bawarjan Schatlo
- Department of Neurosurgery, University Medical Center Göttingen, 37099, Göttingen, Germany
| | | | - Stefan Wiemann
- Division of Molecular Genome Analysis, German Cancer Research Center, 69120, Heidelberg, Germany
| | - Tobias Pukrop
- Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany
- Department of Internal Medicine III, Hematology and Medical Oncology, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Tim Beißbarth
- Department of Medical Bioinformatics, University Medical Center Göttingen, 37099, Göttingen, Germany
| | - Claudia Binder
- Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany
| | - Annalen Bleckmann
- Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, 48149, Münster, Germany.
- West German Cancer Center, University Hospital Münster, 48149, Münster, Germany.
- Department of Hematology/Medical Oncology, University Medical Center Göttingen, 37099, Göttingen, Germany.
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Cell line-directed breast cancer research based on glucose metabolism status. Biomed Pharmacother 2021; 146:112526. [PMID: 34906774 DOI: 10.1016/j.biopha.2021.112526] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 12/06/2021] [Accepted: 12/08/2021] [Indexed: 12/12/2022] Open
Abstract
Metabolic reprogramming is a potential hallmark of tumor cells to support continuous proliferation. Metabolic heterogeneity in breast cancer patients has been highlighted as the driving cause of tumor progression and resistance to anticancer drugs. Studying and identifying distinct metabolic alterations in breast cancer subtypes could offer new perspectives for faster diagnosis and treatment. Given cancer cell dependency on glycolysis, the primary energy source, this enzymatic pathway will play a critical role in targeting therapies. Knowledge about the specific metabolic dependencies of tumors for growth and proliferation can be promising for novel targeted and cell-based therapies. Here, the metabolic status with emphasis on glycolysis of breast cancer cell lines according to their classification was reviewed.
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50
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Mourragui SMC, Loog M, Vis DJ, Moore K, Manjon AG, van de Wiel MA, Reinders MJT, Wessels LFA. Predicting patient response with models trained on cell lines and patient-derived xenografts by nonlinear transfer learning. Proc Natl Acad Sci U S A 2021; 118:e2106682118. [PMID: 34873056 PMCID: PMC8670522 DOI: 10.1073/pnas.2106682118] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/18/2021] [Indexed: 12/13/2022] Open
Abstract
Preclinical models have been the workhorse of cancer research, producing massive amounts of drug response data. Unfortunately, translating response biomarkers derived from these datasets to human tumors has proven to be particularly challenging. To address this challenge, we developed TRANSACT, a computational framework that builds a consensus space to capture biological processes common to preclinical models and human tumors and exploits this space to construct drug response predictors that robustly transfer from preclinical models to human tumors. TRANSACT performs favorably compared to four competing approaches, including two deep learning approaches, on a set of 23 drug prediction challenges on The Cancer Genome Atlas and 226 metastatic tumors from the Hartwig Medical Foundation. We demonstrate that response predictions deliver a robust performance for a number of therapies of high clinical importance: platinum-based chemotherapies, gemcitabine, and paclitaxel. In contrast to other approaches, we demonstrate the interpretability of the TRANSACT predictors by correctly identifying known biomarkers of targeted therapies, and we propose potential mechanisms that mediate the resistance to two chemotherapeutic agents.
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Affiliation(s)
- Soufiane M C Mourragui
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
- Department of Electrical Engineering, Mathematics and Computer Science, Delft University of Technology, 2628 XE Delft, The Netherlands
| | - Marco Loog
- Department of Electrical Engineering, Mathematics and Computer Science, Delft University of Technology, 2628 XE Delft, The Netherlands
- Department of Computer Science, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Daniel J Vis
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| | - Kat Moore
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| | - Anna G Manjon
- Division of Cell Biology, Oncode Institute, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
| | - Mark A van de Wiel
- Epidemiology and Biostatistics, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands
- Medical Research Council Biostatistics Unit, Cambridge University, Cambridge CB2 0SR, United Kingdom
| | - Marcel J T Reinders
- Department of Electrical Engineering, Mathematics and Computer Science, Delft University of Technology, 2628 XE Delft, The Netherlands;
- Leiden Computational Biology Center, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands
| | - Lodewyk F A Wessels
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands;
- Department of Electrical Engineering, Mathematics and Computer Science, Delft University of Technology, 2628 XE Delft, The Netherlands
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