Molecular Cancer Research最新文献

{"title":"Intra- and Extrahepatic Cholangiocarcinomas Display Differing Sensitivities to NK Cell Lysis and Modulate NK Cell Function through Shared and Distinct Pathways.","authors":"Ngan Nguyen, Ian C Henrich","doi":"10.1158/1541-7786.MCR-24-0299","DOIUrl":"10.1158/1541-7786.MCR-24-0299","url":null,"abstract":"<p><p>Cholangiocarcinoma (CCA) is a rare cancer that arises from the bile duct and is broadly classified by the location of the tumor as either intrahepatic cholangiocarcinoma (iCCA) or extrahepatic cholangiocarcinoma (eCCA). Immunotherapy has revolutionized cancer treatment, yet its utility in CCA has been limited as the tumor microenvironment (TME) in CCA is poorly understood compared with other common cancers. Utilizing previously published transcriptome data, our reanalysis has revealed that CCA has one of the highest relative levels of NK cells, a potent cytotoxic immune cell, compared with other cancers. However, despite iCCA and eCCA having comparable relative levels of NK infiltration, NK cell infiltration only correlated with survival in patients with eCCA. Our subsequent investigation revealed that although iCCA and eCCA profoundly altered NK activity, eCCA had a significantly reduced impact on NK functionality. Whereas iCCA was resistant to long-term NK coculture, eCCA was markedly more sensitive. Moreover, although both iCCA and eCCA dysregulated key NK-activating receptors, eCCA coculture did not impact NKp30 nor NKp44 expression. Furthermore, tumor transcriptome analysis of NKHigh CCA samples revealed a modulation of multiple immune and nonimmune cell types within the TME. Implications: These studies are the first to investigate how iCCA and eCCA impact NK cell functionality through shared and distinct mechanisms and how elevated NK cell infiltration could shape the CCA TME in a subtype-dependent manner.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"155-168"},"PeriodicalIF":4.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ASAP1 and ARF1 Regulate Myogenic Differentiation in Rhabdomyosarcoma by Modulating TAZ Activity.","authors":"Katie E Hebron, Olivia L Perkins, Angela Kim, Xiaoying Jian, Sofia A Girald-Berlingeri, Haiyan Lei, Jack F Shern, Elizabeth A Conner, Paul A Randazzo, Marielle E Yohe","doi":"10.1158/1541-7786.MCR-24-0490","DOIUrl":"10.1158/1541-7786.MCR-24-0490","url":null,"abstract":"<p><p>Despite aggressive, multimodal therapies, the prognosis of patients with refractory or recurrent rhabdomyosarcoma (RMS) has not improved in four decades. Because RMS resembles skeletal muscle precursor cells, differentiation-inducing therapy has been proposed for patients with advanced disease. In RAS-mutant PAX fusion-negative RMS (FN-RMS) preclinical models, MEK1/2 inhibition (MEKi) induces differentiation, slows tumor growth, and extends survival. However, the response is short-lived. A better understanding of the molecular mechanisms regulating FN-RMS differentiation could improve differentiation therapy. In this study, we identified a role in FN-RMS differentiation for ASAP1, an ADP ribosylation factor (ARF) GTPase-activating protein (GAP) with both proinvasive and tumor-suppressor functions. We found that ASAP1 knockdown inhibited differentiation in FN-RMS cells. Interestingly, knockdown of the GTPases ARF1 or ARF5, targets of ASAP1 GAP activity, also blocked differentiation of FN-RMS. We discovered that loss of ARF pathway components blocked myogenic transcription factor expression. Therefore, we examined the effects on transcriptional regulators. MEKi led to the phosphorylation and inactivation of WW domain-containing transcriptional regulator 1 (WWTR1; TAZ), a homolog of the pro-proliferative transcriptional co-activator YAP1, regulated by the Hippo pathway. However, loss of ASAP1 or ARF1 blocked this inactivation, which inhibits MEKi-induced differentiation. Finally, MEKi-induced differentiation was rescued by dual knockdown of ASAP1 and WWTR1. This study shows that ASAP1 and ARF1 are necessary for myogenic differentiation, providing a deeper understanding of differentiation in FN-RMS and illuminating an opportunity to advance differentiation therapy. Implications: ASAP1 and ARF1 regulate MEKi-induced differentiation of FN-RMS cells by modulating WWTR1 (TAZ) activity, supporting YAP1/TAZ inhibition as a FN-RMS differentiation therapy strategy.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"95-106"},"PeriodicalIF":4.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11799837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PRMT5 Maintains Tumor Stem Cells to Promote Pediatric High-Grade Glioma Tumorigenesis.","authors":"John DeSisto, Ilango Balakrishnan, Aaron J Knox, Gabrielle Link, Sujatha Venkataraman, Rajeev Vibhakar, Adam L Green","doi":"10.1158/1541-7786.MCR-24-0233","DOIUrl":"10.1158/1541-7786.MCR-24-0233","url":null,"abstract":"<p><p>Pediatric high-grade gliomas (PHGG) are aggressive, undifferentiated central nervous system tumors with poor outcomes, for which no standard-of-care drug therapy currently exists. Through a knockdown (KD) screen for epigenetic regulators, we identified PRMT5 as essential for PHGG cell growth. We hypothesized that, similar to its effect in normal cells, PRMT5 promotes self-renewal of stem-like PHGG tumor-initiating cells essential for tumor growth. We conducted in vitro analyses, including limiting dilution studies of self-renewal, to determine the phenotypic effects of PRMT5 KD. We performed chromatin immunoprecipitation sequencing (ChIP-Seq) to identify PRMT5-mediated epigenetic changes and performed gene set enrichment analysis to identify pathways that PRMT5 regulates. Using an orthotopic xenograft model of PHGG, we tracked survival and histologic characteristics resulting from PRMT5 KD or administration of a PRMT5 inhibitor ± radiation therapy. In vitro, PRMT5 KD slowed cell-cycle progression, tumor growth and self-renewal, and altered chromatin occupancy at genes associated with differentiation, tumor formation, and growth. In vivo, PRMT5 KD increased survival and reduced tumor aggressiveness; however, pharmacologic inhibition of PRMT5 with or without radiation therapy did not improve survival. PRMT5 KD epigenetically reduced tumor-initiating cells' self-renewal, leading to increased survival in preclinical models. Pharmacologic inhibition of PRMT5 enzymatic activity may have failed in vivo due to insufficient reduction of PRMT5 activity by chemical inhibition, or this failure may suggest that nonenzymatic activities of PRMT5 are more relevant. Implications: PRMT5 maintains and promotes the growth of stem-like cells that initiate and drive tumorigenesis in PHGG.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"107-118"},"PeriodicalIF":4.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11799838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATAD2 Drives Prostate Cancer Progression to Metastasis.","authors":"Anindita Dutta, Antonio Rodriguez-Calero, Kacey Ronaldson-Bouchard, Anne Offermann, Daoud Rahman, Twinkle Bapuji Vhatkar, Dan Hasson, Mohammed Alshalalfa, Elai Davicioni, R Jeffrey Karnes, Mark A Rubin, Gordana Vunjak-Novakovic, Cory Abate-Shen, Juan Martin Arriaga","doi":"10.1158/1541-7786.MCR-24-0544","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0544","url":null,"abstract":"<p><p>Metastasis accounts for the overwhelming majority of cancer deaths. In prostate cancer and many other solid tumors, progression to metastasis is associated with drastically reduced survival outcomes, yet the mechanisms behind this progression remain largely unknown. ATAD2 (ATPase family AAA domain containing 2) is an epigenetic reader of acetylated histones that is overexpressed in multiple cancer types and usually associated with poor patient outcomes. However, the functional role of ATAD2 in cancer progression and metastasis has been relatively understudied. Here we employ genetically engineered mouse models of prostate cancer bone metastasis, as well as multiple independent human cohorts, to show that ATAD2 is highly enriched in bone metastasis compared to primary tumors and significantly associated with the development of metastasis. We show that ATAD2 expression is associated with MYC pathway activation in patient datasets and that, at least in a subset of tumors, MYC and ATAD2 can regulate each other's expression. Using functional studies on mouse bone metastatic cell lines and innovative organ-on-a-chip bone invasion assays, we establish a functional role for ATAD2 inhibition in diminishing prostate cancer metastasis and growth in bone. Implications: Our study highlights ATAD2 as a driver of prostate cancer progression and metastasis and suggests it may constitute a promising novel therapeutic target.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor microenvironment: obstacles and opportunities for T-cell based tumor immunotherapies.","authors":"Miao-Miao Hu, Ying Zhao, Nan Zhang, Fang-Yuan Gong, Wei Zhang, Chun-Sheng Dong, Jian-Feng Dai, Jun Wang","doi":"10.1158/1541-7786.MCR-24-0747","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0747","url":null,"abstract":"<p><p>The complex composition and dynamic change of the tumor microenvironment (TME), mainly consisting of tumor cells, immune cells, stromal cells and extracellular components, significantly impedes the effector function of cytotoxic T cells (CTLs) and thus represents a major obstacle for tumor immunotherapies. In this review, we summarize and discuss the impacts and underlying mechanisms of major elements in the TME (different cell types, extracellular matrix, nutrients and metabolites, etc.) on the infiltration, survival and effector functions of T cells, mainly CD8+ CTLs. Moreover, we also highlight recent advances that may potentiate endogenous anti-tumor immunity and improve the efficacy of T-cell based immunotherapies in cancer patients by manipulating components inside/outside of the TME. A deeper understanding of the effects and action mechanisms of TME components on the tumor-eradicating ability of CTLs may pave the way for discovering new targets to augment endogenous anti-tumor immunity and for designing combinational therapeutic regimens to enhance the efficacy of tumor immunotherapies in clinic.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exome sequencing reveals a sparse genomic landscape in Kaposi sarcoma.","authors":"Warren Phipps, Bhavneet Bhinder, Andrea Towlerton, Peter Mooka, James Kafeero, Matt Fitzgibbon, Olivier Elemento, Ethel Cesarman","doi":"10.1158/1541-7786.MCR-24-0373","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0373","url":null,"abstract":"<p><p>Kaposi Sarcoma (KS) is a frequently aggressive malignancy caused by Kaposi sarcoma herpesvirus (KSHV/HHV-8). People with immunodeficiencies, including HIV, are at increased risk for developing KS, but our understanding of the contributions of the cellular genome to KS pathogenesis remains limited. To determine if there are cellular genetic alterations in KS that might provide biological or therapeutic insights, we performed whole exome sequencing on 78 KS tumors and matched normal control skin from 59 adults with KS (46 with HIV-associated KS and 13 with HIV-negative KS) receiving treatment at the Uganda Cancer Institute in Kampala, Uganda. We found a very low mutational burden in all but one specimen (median=11 mutations), which is the lowest number of mutations among all 33 tumor types in The Cancer Genome Atlas (TCGA). No recurrent mutations were seen and the most commonly affected oncogenic pathway was RTK/RAS. Mutational signatures included defective DNA mismatch repair and smoking. There was no evidence suggesting that multiple tumors from the same patient originated from the same original clone. The number of genome copy alterations per genome were higher in tumors from those without HIV infection and in tumors from participants with advanced stage disease, suggesting that lesions that take longer to develop may accumulate more alterations, although the number of alterations remain low compared to other cancers. Implications: Our findings indicate that the pathogenesis of KS differs from other malignancies, and that the primary driver of carcinogenesis is KSHV viral infection and expression of viral oncogenes, rather than clonal oncogenic transformation.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"THG-1/TSC22D4 promotes interleukin-1 signaling through stabilization of TRAF6 in squamous cell carcinoma.","authors":"Yasuhito Okano, Hiroyuki Suzuki, Yukihide Watanabe, Mohammed Abdelaziz, Lev Manevich, Kunio Kawanishi, Haruka Ozaki, Ryota Ishii, Shin Matsumoto, Nohara Goto, Ling Zheng, Yukari Okita, Jongchan Hwang, Masahiro Nakayama, Yoshihide Shima, Noriaki Sakamoto, Masayuki Noguchi, Keiji Tabuchi, Mitsuyasu Kato","doi":"10.1158/1541-7786.MCR-24-0120","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0120","url":null,"abstract":"<p><p>Malignant neoplasms arise within a region of chronic inflammation caused by tissue injuries. Inflammation is a key factor involved in all aspects of tumorigenesis including initiation, proliferation, invasion, angiogenesis, and metastasis. Interleukin-1 (IL-1) plays critical functions in tumor development with influencing the tumor microenvironment and promoting cancer progression. However, the mechanism of continuous activation of IL-1-mediated inflammatory pathway in tumor has not been fully elucidated. This study provides a novel mechanism of the autocrine activation of IL-1 signaling in squamous cell carcinoma (SCC) through a novel oncoprotein, TSC-22 homologous gene-1 (THG-1, also known as TSD22D4). The RNA sequencing analysis revealed that THG-1 overexpression enhances the transcription of NF-κB targets including IL1A, IL1B, TNFA, and IL8. Furthermore, THG-1 knockdown reduced the responsiveness to IL-1 through suppression of NF-κB nuclear translocation. To elucidate the mechanism, we focused on a THG-1 interacting protein, NRBP1. We found that NRBP1 facilitates the degradation of TRAF6 through its E3 ubiquitin ligase activity. THG-1 bound to NRBP1 and suppressed the degradation of TRAF6. Furthermore, THG-1 knockdown reduced TRAF6 abundance and NF-κB activity in SCC cells. Public database analyses of head and neck SCC revealed that high expression of THG-1 is associated with activation of the IL-1 and TNF pathways, which share TRAF6 in the signal transductions. Finally, THG-1 abundance in laryngeal SCC specimens is elevated in patients with recurrence. These results indicated that THG-1 drives the self-sufficiency of IL-1-mediated inflammatory pathway, which could contribute to the future diagnosis and immune therapy of SCCs. Implications: An oncoprotein THG-1/TSD22D4 activates the IL-1-mediated inflammatory pathway through suppression of TRAF6 degradation, which mediates the continuous inflammation in tumors.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of WDR77 in Cancer: More Than a PRMT5 Interactor.","authors":"Isaac Silverman, Aaron Shaykevich, Radhashree Maitra","doi":"10.1158/1541-7786.MCR-24-0933","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0933","url":null,"abstract":"<p><p>WD repeat domain 77 protein (WDR77), a WD-40 domain-containing protein, is a crucial regulator of cellular pathways in cancer progression. While much of the past research on WDR77 has focused on its interaction with PRMT5 in histone methylation, WDR77's regulatory functions extend beyond this pathway, influencing diverse mechanisms such as mRNA translation, chromatin assembly, cell cycle regulation, and apoptosis. WDR77 is a key regulator of cell cycle progression, regulating the transition from the G1 phase. WDR77 regulates many signaling pathways such as TGFβ where its role in these cellular pathways underscores its broad oncogenic potential. WDR77 also assists and promotes certain transcription factors such as E2F. Furthermore, in certain cancers, WDR77 enhances steroid hormone receptor activity, uniquely linking it to hormone-driven malignancies. WDR77 often translocates between the nucleus and the cytoplasm, with its location dictating its role in the cell. WDR77 has the ability to adapt its function depending on its location which emphasizes its dynamic role in both promoting and inhibiting tumor growth, depending on cellular context. This dual function makes WDR77 an attractive therapeutic target, as disrupting its interactions with critical signaling pathways or modulating its translocation could yield novel strategies for cancer treatment. Given WDR77's role in oncogenic pathways independent of PRMT5, further exploration of WDR77 and its non-PRMT5-related activities may reveal additional therapeutic opportunities in an array of cancers.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143033758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploiting YES1-driven EGFR expression improves the efficacy of EGFR inhibitors.","authors":"Leslie Cuellar-Vite, Elyse M Donaubauer, Kristen L Weber-Bonk, Jessica R Bobbitt, Natasha N Ingles, Taylor L Brzozowski, Fadi W Abdul-Karim, Christine N Booth, Ruth A Keri","doi":"10.1158/1541-7786.MCR-24-0309","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0309","url":null,"abstract":"<p><p>Epidermal growth factor receptor (EGFR) is a highly expressed driver of many cancers, yet the utility of EGFR inhibitors is limited to cancers that harbor sensitizing mutations in the EGFR gene due to dose limiting toxicities. Rather than conventionally blocking the kinase activity of EGFR, we sought to reduce its transcription as an alternative approach to broaden the therapeutic window for EGFR inhibitors targeting wildtype or mutant EGFR. We found that YES1 is highly expressed in triple negative breast cancer (TNBC) and drives cell growth by elevating EGFR levels. Mechanistically, YES1 stimulates EGFR expression by signaling to JNK and stabilizing the AP-1 transcription factor, c-Jun. This effect extends beyond TNBC as YES1 also sustains EGFR expression in non-small cell lung cancer (NSCLC) cells, including those that harbor the EGFR gatekeeper mutation, T790M. The novel ability of YES1 to regulate the expression of wildtype and mutant EGFR mRNA and protein provides a potential therapeutic opportunity of utilizing YES1 blockade to broadly increase the efficacy of EGFR inhibitors. Indeed, we found synergy within in vitro and in vivo models of TNBC and NSCLC, even in the absence of EGFR activating mutations. Together, these data provide a rationale for blocking YES1 activity as an approach for improving the efficacy of EGFR-targeting drugs in cancers that have generally been refractory to such inhibitors. Implications: YES1 sustains EGFR expression, revealing a therapeutic vulnerability for increasing the efficacy of EGFR inhibitors by lowering the threshold for efficacy in tumors driven by wildtype or mutant receptor.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying and targeting key driver genes for collagen production within the 11q13/14 breast cancer amplicon.","authors":"Daniela Araiza-Olivera, Tatiana Y Prudnikova, Cristina Uribe-Alvarez, Kathy Q Cai, Janusz Franco-Barraza, Jesus M Dones, Ronald T Raines, Jonathan Chernoff","doi":"10.1158/1541-7786.MCR-24-0331","DOIUrl":"10.1158/1541-7786.MCR-24-0331","url":null,"abstract":"<p><p>Breast cancers of the IntClust-2 type, characterized by amplification of a small portion of chromosome 11, have a median survival of only five years. Several cancer-relevant genes occupy this portion of chromosome 11, and it is thought that overexpression of a combination of driver genes in this region is responsible for the poor outcome of women in this group. In this study we used a gene editing method to knock out, one by one, each of 198 genes that are located within the amplified region of chromosome 11 and determined how much each of these genes contributed to the survival of breast cancer cells. In addition to well-known drivers such as CCND1 and PAK1, we identified two different genes (SERPINH1 and P4HA3), that encode proteins involved in collagen synthesis and organization. Using both in vitro and in vivo functional analyses, we determined that P4HA3 and/or SERPINH1 provide a critical driver function on IntClust-2 basic processes, such as viability, proliferation, and migration. Inhibiting these enzymes via genetic or pharmacologic means reduced collagen synthesis and impeded oncogenic signaling transduction in cell culture models, and a small-molecule inhibitor of P4HA3 was effective in treating 11q13 tumor growth in an animal model. As collagen has a well-known association with tissue stiffness and aggressive forms of breast cancer, we believe that the two genes we identified provide an opportunity for a new therapeutic strategy in IntClust-2 breast cancers. Implications: Breast cancers with 11q13/14 chromosomal amplifications may be vulnerable to inhibitors of collagen synthesis.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}