Cancer research最新文献_第3页

Modeling Drug Responses and Evolutionary Dynamics using Patient-Derived Xenografts Reveals Precision Medicine Strategies for Triple Negative Breast Cancer 利用患者衍生异种移植物模拟药物反应和进化动态，揭示三阴性乳腺癌的精准医疗策略

IF 11.2 1区医学

Cancer research Pub Date : 2024-11-08 DOI: 10.1158/0008-5472.can-24-1703

Abigail Shea, Yaniv Eyal-Lubling, Daniel Guerrero-Romero, Raquel Manzano Garcia, Wendy Greenwood, Martin O’Reilly, Dimitra Georgopoulou, Maurizio Callari, Giulia Lerda, Sophia Wix, Agnese Giovannetti, Riccardo Masina, Elham Esmaeilishirazifard, Wei Cope, Alistair G. Martin, Ai Nagano, Lisa Young, Steven Kupczak, Yi Cheng, Helen Bardwell, Elena Provenzano, Justine Kane, Jonny Lay, Louise Grybowicz, Karen McAdam, Carlos Caldas, Jean Abraham, Oscar M. Rueda, Alejandra Bruna

{"title":"Modeling Drug Responses and Evolutionary Dynamics using Patient-Derived Xenografts Reveals Precision Medicine Strategies for Triple Negative Breast Cancer","authors":"Abigail Shea, Yaniv Eyal-Lubling, Daniel Guerrero-Romero, Raquel Manzano Garcia, Wendy Greenwood, Martin O’Reilly, Dimitra Georgopoulou, Maurizio Callari, Giulia Lerda, Sophia Wix, Agnese Giovannetti, Riccardo Masina, Elham Esmaeilishirazifard, Wei Cope, Alistair G. Martin, Ai Nagano, Lisa Young, Steven Kupczak, Yi Cheng, Helen Bardwell, Elena Provenzano, Justine Kane, Jonny Lay, Louise Grybowicz, Karen McAdam, Carlos Caldas, Jean Abraham, Oscar M. Rueda, Alejandra Bruna","doi":"10.1158/0008-5472.can-24-1703","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1703","url":null,"abstract":"The inter- and intra-tumor heterogeneity of triple negative breast cancers (TNBC), which is reflected in diverse drug responses, interplays with tumor evolution. Here, we developed a preclinical experimental and analytical framework using treatment-naive TNBC patient-derived tumor xenografts (PDTX) to test their predictive value in personalized cancer treatment approaches. Patients and their matched PDTX exhibited concordant drug responses to neoadjuvant therapy using two trial designs and dosing schedules. This platform enabled analysis of non-genetic mechanisms involved in relapse dynamics. Treatment resulted in permanent phenotypic changes with functional and therapeutic consequences. High throughput drug screening methods in ex vivo patient derived tumor xenograft cells (PDTCs) revealed patient-specific drug response changes dependent on first-line therapy. This was validated in vivo, as exemplified by a change in olaparib sensitivity in tumors previously treated with clinically relevant cycles of standard-of-care chemotherapy. In summary, PDTXs provide a robust tool to test patient drug responses and therapeutic regimens and to model evolutionary trajectories. However, high inter-model variability and permanent non-genomic transcriptional changes constrain their use for personalized cancer therapy. This work highlights important considerations associated with preclinical drug response modeling and potential uses of the platform to identify efficacious and preferential sequential therapeutic regimens.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"1 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CSTF2 Supports Hypoxia Tolerance in Hepatocellular Carcinoma by Enabling m6A Modification Evasion of PGK1 to Enhance Glycolysis CSTF2 通过使 m6A 修饰逃避 PGK1 来增强糖酵解，从而支持肝细胞癌的缺氧耐受性

IF 11.2 1区医学

Cancer research Pub Date : 2024-11-08 DOI: 10.1158/0008-5472.can-24-2283

Qiangnu Zhang, Yusen Zhang, Chuli Fu, Xiaoyan He, Zuotian Huang, Geyan Wu, Teng Wei, Wen Jin, Lesen Yan, Meilong Wu, Gongze Peng, LinLan Fan, Mingyue Li, Yuehua Guo, Jiangang Bi, Yu Bai, Stephanie Roessler, Guang-Rong Yan, Liping Liu

{"title":"CSTF2 Supports Hypoxia Tolerance in Hepatocellular Carcinoma by Enabling m6A Modification Evasion of PGK1 to Enhance Glycolysis","authors":"Qiangnu Zhang, Yusen Zhang, Chuli Fu, Xiaoyan He, Zuotian Huang, Geyan Wu, Teng Wei, Wen Jin, Lesen Yan, Meilong Wu, Gongze Peng, LinLan Fan, Mingyue Li, Yuehua Guo, Jiangang Bi, Yu Bai, Stephanie Roessler, Guang-Rong Yan, Liping Liu","doi":"10.1158/0008-5472.can-24-2283","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2283","url":null,"abstract":"Cleavage stimulation factor subunit 2 (CSTF2) is a fundamental factor in the regulation of 3'-end cleavage and alternative polyadenylation of pre-mRNAs. Previous work has identified a tumor-promoting role of CSTF2, suggesting that it may represent a potential therapeutic target. Here, we aimed to elucidate the mechanistic function of CSTF2 in hepatocellular carcinoma (HCC). CSTF2 upregulation was frequent in HCC, and elevated levels of CSTF2 correlated with poor patient prognosis. While CSTF2 inhibition did not suppress HCC growth under non-stress conditions, it supported tolerance and survival of HCC cells under hypoxic conditions. Mechanistically, CSTF2 increased PGK1 protein production to enhance glycolysis, thereby sustaining the energy supply under hypoxic conditions. CSTF2 shortened the 3' untranslated region (3' UTR) of phosphoglycerate kinase 1 (PGK1) pre-mRNA by binding near the proximal polyadenylation site (pPAS). This shortening led to a loss of N6-methyladenosine (m6A) modification sites that are bound by YTH N6-methyladenosine RNA-binding protein F2 (YTHDF2) and increase degradation of PGK1 mRNA. Concurrently, hypoxia increased m6A modification of PGK1 mRNA near the pPAS that was recognized by the YTH N6-methyladenosine RNA-binding protein C1 (YTHDC1), which recruited CSTF2 to enhance the shortening of the PGK1 3’-UTR. A small molecule screen identified masitinib as an inhibitor of CSTF2. Masitinib counteracted PGK1 upregulation by CSTF2 and suppressed the growth of HCC xenograft and patient-derived organoid models. In conclusion, this study revealed a function of CSTF2 in supporting HCC survival under hypoxia conditions through m6A modification evasion and metabolic reprogramming, indicating inhibiting CSTF2 may overcome hypoxia tolerance in HCC.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"14 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Fluorescence Lifetime Imaging Enables In vivo Quantification of PD-L1 Expression and Inter-tumoral Heterogeneity 荧光寿命成像可对 PD-L1 表达和肿瘤间异质性进行体内定量分析

IF 11.2 1区医学

Cancer research Pub Date : 2024-11-08 DOI: 10.1158/0008-5472.can-24-0880

Rahul Pal, Murali Krishnamoorthy, Aya Matsui, Homan Kang, Satoru Morita, Hajime Taniguchi, Tatsuya Kobayashi, Atsuyo Morita, Hak Soo Choi, Dan G. Duda, Anand T.N. Kumar

{"title":"Fluorescence Lifetime Imaging Enables In vivo Quantification of PD-L1 Expression and Inter-tumoral Heterogeneity","authors":"Rahul Pal, Murali Krishnamoorthy, Aya Matsui, Homan Kang, Satoru Morita, Hajime Taniguchi, Tatsuya Kobayashi, Atsuyo Morita, Hak Soo Choi, Dan G. Duda, Anand T.N. Kumar","doi":"10.1158/0008-5472.can-24-0880","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0880","url":null,"abstract":"Patient selection for cancer immunotherapy requires precise, quantitative readouts of biomarker expression in intact tumors that can be reliably compared across multiple subjects over time. The current clinical standard biomarker for assessing immunotherapy response is programmed death-ligand-1 (PD-L1) expression, typically quantified using immunohistochemistry. This method, however, only provides snapshots of PD-L1 expression status in microscopic regions of ex vivo specimens. While various targeted probes have been investigated for in vivo imaging of PD-L1, non-specific probe accumulation within the tumor microenvironment (TME) has hindered accurate quantification, limiting the utility for preclinical and clinical studies. Here, we demonstrated that in vivo time-domain (TD) fluorescence imaging of an anti-PD-L1 antibody tagged with the near-infrared fluorophore IRDye 800CW (αPDL1-800) can yield quantitative estimates of baseline tumor PD-L1 heterogeneity across untreated mice, as well as variations in PD-L1 expression in mice undergoing clinically relevant anti-PD1 treatment. The fluorescence lifetime (FLT) of PD-L1 bound αPDL1-800 was significantly longer than the FLT of nonspecifically accumulated αPDL1-800 in the TME. This FLT contrast allowed quantification of PD-L1 expression across mice both in superficial breast tumors using planar FLT imaging and in deep-seated liver tumors (&gt;5 mm depth) using the asymptotic TD algorithm for fluorescence tomography. These findings suggest that fluorescence lifetime imaging can accelerate the preclinical investigation and clinical translation of new immunotherapy treatments by enabling robust quantification of receptor expression across subjects.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"70 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142598082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Spatial and Single Cell Analyses Reveal Heterogeneity of DNAM-1 Receptor-Ligand Interactions that Instructs Intratumoral γδT-Cell Activity 空间和单细胞分析揭示了 DNAM-1 受体与配体相互作用的异质性，这种异质性可指导瘤内γδT 细胞的活动

IF 11.2 1区医学

Cancer research Pub Date : 2024-11-08 DOI: 10.1158/0008-5472.can-24-1509

Xiaolin Wang, Hui Wang, Zhengjing Lu, Xiangjun Liu, Wenjia Chai, Wei Wang, Jun Feng, Shen Yang, Wei Yang, Haiyan Cheng, Chenghao Chen, Shihan Zhang, Nian Sun, Qiaoyin Liu, Qiliang Li, Wenqi Song, Fang Jin, Qi Zeng, Shengcai Wang, Yan Su, Huanmin Wang, Xin Ni, Jingang Gui

{"title":"Spatial and Single Cell Analyses Reveal Heterogeneity of DNAM-1 Receptor-Ligand Interactions that Instructs Intratumoral γδT-Cell Activity","authors":"Xiaolin Wang, Hui Wang, Zhengjing Lu, Xiangjun Liu, Wenjia Chai, Wei Wang, Jun Feng, Shen Yang, Wei Yang, Haiyan Cheng, Chenghao Chen, Shihan Zhang, Nian Sun, Qiaoyin Liu, Qiliang Li, Wenqi Song, Fang Jin, Qi Zeng, Shengcai Wang, Yan Su, Huanmin Wang, Xin Ni, Jingang Gui","doi":"10.1158/0008-5472.can-24-1509","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1509","url":null,"abstract":"The dynamic interplay between tumor cells and γδT cells within the tumor microenvironment (TME) significantly influences disease progression and immunotherapy outcome. Here, we delved into the modulation of γδT-cell activation by tumor cell ligands CD112 and CD155, which interact with the activating receptor DNAM-1 on γδT cells. Spatial and single cell RNA sequencing (scRNA-seq), as well as spatial metabolome analysis, from neuroblastoma (NB) revealed that the expression levels and localization of CD112 and CD155 varied across and within tumors, correlating with differentiation status, metabolic pathways, and ultimately disease prognosis and patient survival. Both in vivo tumor xenograft experiments and in vitro co-culture experiments demonstrated that a high CD112/CD155 expression ratio in tumors enhanced γδT-cell-mediated cytotoxicity, while a low-ratio fostered tumor resistance. Mechanistically, CD112 sustained DNAM-1-mediated γδT-cell activation, whereas CD155 downregulated DNAM-1 expression via TRIM21-mediated ubiquitin proteasomal degradation. By interacting with tumor cells differentially expressing CD112 and CD155, intratumoral γδT cells exhibited varying degrees of activation and DNAM-1 expression, representing three major functional subsets. This study underscores the complexity of tumor-immune crosstalk, offering insights into how tumor heterogeneity shapes the immune landscape.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"9 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Peritumoral Venous Vessels: Autobahn and Portal for T cells to Melanoma Brain Metastasis 瘤周静脉血管：T细胞通往黑色素瘤脑转移灶的高速公路和门户

IF 11.2 1区医学

Cancer research Pub Date : 2024-11-08 DOI: 10.1158/0008-5472.can-24-4054

Benjamin Izar, Minah Kim

引用次数: 0

FOXP4 Is a Direct YAP1 Target That Promotes Gastric Cancer Stemness and Drives Metastasis. FOXP4是YAP1的直接靶标，可促进胃癌干细胞生长并推动转移

IF 12.5 1区医学

Cancer research Pub Date : 2024-11-04 DOI: 10.1158/0008-5472.CAN-23-3074

Xiaoli Liu, Bonan Chen, Fuda Xie, Kit Yee Wong, Alvin H K Cheung, Jinglin Zhang, Qian Wu, Canbin Fang, Jintao Hu, Shouyu Wang, Dazhi Xu, Jianwu Chen, Yuzhi Wang, Chi Chun Wong, Huarong Chen, William K K Wu, Jun Yu, Michael W Y Chan, Chi Man Tsang, Kwok Wai Lo, Gary M K Tse, Ka-Fai To, Wei Kang

{"title":"FOXP4 Is a Direct YAP1 Target That Promotes Gastric Cancer Stemness and Drives Metastasis.","authors":"Xiaoli Liu, Bonan Chen, Fuda Xie, Kit Yee Wong, Alvin H K Cheung, Jinglin Zhang, Qian Wu, Canbin Fang, Jintao Hu, Shouyu Wang, Dazhi Xu, Jianwu Chen, Yuzhi Wang, Chi Chun Wong, Huarong Chen, William K K Wu, Jun Yu, Michael W Y Chan, Chi Man Tsang, Kwok Wai Lo, Gary M K Tse, Ka-Fai To, Wei Kang","doi":"10.1158/0008-5472.CAN-23-3074","DOIUrl":"10.1158/0008-5472.CAN-23-3074","url":null,"abstract":"The Hippo-YAP1 pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration. Dysregulation of Hippo-YAP1 signaling promotes initiation and progression of several types of cancer, including gastric cancer. As the Hippo-YAP1 pathway regulates expression of thousands of genes, it is important to establish which target genes contribute to the oncogenic program driven by YAP1 to identify strategies to circumvent it. In this study, we identified a vital role of forkhead box protein 4 (FOXP4) in YAP1-driven gastric carcinogenesis by maintaining stemness and promoting peritoneal metastasis. Loss of FOXP4 impaired gastric cancer spheroid formation and reduced stemness marker expression, whereas FOXP4 upregulation potentiated cancer cell stemness. RNA sequencing analysis revealed SOX12 as a downstream target of FOXP4, and functional studies established that SOX12 supports stemness in YAP1-induced carcinogenesis. A small-molecule screen identified 42-(2-tetrazolyl) rapamycin as a FOXP4 inhibitor, and targeting FOXP4 suppressed gastric cancer tumor growth and enhanced the efficacy of 5-fluorouracil chemotherapy in vivo. Collectively, these findings revealed that FOXP4 upregulation by YAP1 in gastric cancer regulates stemness and tumorigenesis by upregulating SOX12. Targeting the YAP1-FOXP4-SOX12 axis represents a potential therapeutic strategy for gastric cancer. Significance: Hippo-YAP1 signaling maintains stemness in gastric cancer by upregulating FOXP4, identifying FOXP4 as a stemness biomarker and therapeutic target that could help improve patient outcomes.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"3574-3588"},"PeriodicalIF":12.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11532785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction: Quantitative Spatial Profiling of Immune Populations in Pancreatic Ductal Adenocarcinoma Reveals Tumor Microenvironment Heterogeneity and Prognostic Biomarkers. 更正：胰腺导管腺癌免疫群体的定量空间谱分析揭示了肿瘤微环境异质性和预后生物标志物。

IF 12.5 1区医学

Cancer research Pub Date : 2024-11-04 DOI: 10.1158/0008-5472.CAN-24-2929

Haoyang Mi, Shamilene Sivagnanam, Courtney B Betts, Shannon M Liudahl, Elizabeth M Jaffee, Lisa M Coussens, Aleksander S Popel

引用次数: 0

Targeting BCL2 with Venetoclax Enhances the Efficacy of the KRASG12D Inhibitor MRTX1133 in Pancreatic Cancer. 用 Venetoclax 靶向 BCL2 可增强 KRASG12D 抑制剂 MRTX1133 对胰腺癌的疗效

IF 12.5 1区医学

Cancer research Pub Date : 2024-11-04 DOI: 10.1158/0008-5472.CAN-23-3574

Jeffrey H Becker, Anastasia E Metropulos, Christina Spaulding, Alejandra M Marinelarena, Mario A Shields, Daniel R Principe, Thao D Pham, Hidayatullah G Munshi

{"title":"Targeting BCL2 with Venetoclax Enhances the Efficacy of the KRASG12D Inhibitor MRTX1133 in Pancreatic Cancer.","authors":"Jeffrey H Becker, Anastasia E Metropulos, Christina Spaulding, Alejandra M Marinelarena, Mario A Shields, Daniel R Principe, Thao D Pham, Hidayatullah G Munshi","doi":"10.1158/0008-5472.CAN-23-3574","DOIUrl":"10.1158/0008-5472.CAN-23-3574","url":null,"abstract":"MRTX1133 is currently being evaluated in patients with pancreatic ductal adenocarcinoma (PDAC) tumors harboring a KRASG12D mutation. Combination strategies have the potential to enhance the efficacy of MRTX1133 to further promote cell death and tumor regression. In this study, we demonstrated that MRTX1133 increased the levels of the proapoptotic protein BIM in PDAC cells and conferred sensitivity to the FDA-approved BCL2 inhibitor venetoclax. Combined treatment with MRTX1133 and venetoclax resulted in cell death and growth suppression in 3D cultures. BIM was required for apoptosis induced by the combination treatment. Consistently, BIM was induced in tumors treated with MRTX1133, and venetoclax enhanced the efficacy of MRTX1133 in vivo. Venetoclax could also resensitize MRTX1133-resistant PDAC cells to MRTX1133 in 3D cultures, and tumors established from resistant cells responded to the combination of MRTX1133 and venetoclax. These results provide a rationale for the clinical testing of MRTX1133 and venetoclax in patients with PDAC. Significance: The combination of MRTX1133 and the FDA-approved drug venetoclax promotes cancer cell death and tumor regression in pancreatic ductal adenocarcinoma, providing rationale for testing venetoclax with KRASG12D inhibitors in patients with pancreatic cancer.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"3629-3639"},"PeriodicalIF":12.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11532783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

ASCL1 Drives the Development of Neuroendocrine Prostate Cancer. ASCL1 驱动神经内分泌性前列腺癌的发展

IF 12.5 1区医学

Cancer research Pub Date : 2024-11-04 DOI: 10.1158/0008-5472.CAN-24-2913

Caden N McQuillen, Nicholas J Brady

{"title":"ASCL1 Drives the Development of Neuroendocrine Prostate Cancer.","authors":"Caden N McQuillen, Nicholas J Brady","doi":"10.1158/0008-5472.CAN-24-2913","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-2913","url":null,"abstract":"Therapeutic resistance to androgen receptor (AR)-targeting agents remains a significant clinical problem during the treatment of prostate cancer, with the incidence rate of resistant disease increasing as more men are treated with next-generation AR-targeted therapies. Lineage plasticity and progression to neuroendocrine prostate cancer (NEPC) are mechanisms by which prostate tumors lose dependence on androgen signaling and escape treatment. Although many known genetic alterations can predispose tumors to acquiring the NEPC phenotype, it remains unclear what, if any, drivers are essential to this progression. In this issue of Cancer Research, Rodarte and colleagues identified ASCL1 as one such essential regulator. Through the use of genetically engineered mouse models, the authors demonstrated that whereas ASCL1 was dispensable for tumor formation and growth, ASCL1 loss nearly completely abrogated the development of NEPC and instead redirected lineage trajectories toward a basal-like phenotype. This study provides an important new model for the study of NEPC, reveals the ability of ASCL1+ NEPC cells to also assume a NEUROD1+ state, and demonstrates the changes to tumor cell phenotypes following ASCL1 loss. See related article by Rodarte et al., p. 3522.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"84 21","pages":"3499-3501"},"PeriodicalIF":12.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting YES1 Disrupts Mitotic Fidelity and Potentiates the Response to Taxanes in Triple-Negative Breast Cancer. 靶向 YES1 可破坏有丝分裂的保真度并增强三阴性乳腺癌对紫杉类药物的反应。

IF 12.5 1区医学

Cancer research Pub Date : 2024-11-04 DOI: 10.1158/0008-5472.CAN-23-2558

Katrina M Piemonte, Natasha N Ingles, Kristen L Weber-Bonk, Mitchell J Valentine, Parth R Majmudar, Salendra Singh, Ruth A Keri

{"title":"Targeting YES1 Disrupts Mitotic Fidelity and Potentiates the Response to Taxanes in Triple-Negative Breast Cancer.","authors":"Katrina M Piemonte, Natasha N Ingles, Kristen L Weber-Bonk, Mitchell J Valentine, Parth R Majmudar, Salendra Singh, Ruth A Keri","doi":"10.1158/0008-5472.CAN-23-2558","DOIUrl":"10.1158/0008-5472.CAN-23-2558","url":null,"abstract":"Clinical trials examining broad-spectrum Src family kinase (SFK) inhibitors revealed significant dose-limiting toxicities, preventing advancement for solid tumors. SFKs are functionally heterogeneous, thus targeting individual members is a potential strategy to elicit antitumor efficacy while avoiding toxicity. Here, we identified that YES1 is the most highly overexpressed SFK in triple-negative breast cancer (TNBC) and is associated with poor patient outcomes. Disrupting YES1, genetically or pharmacologically, induced aberrant mitosis, centrosome amplification, multipolar spindles, and chromosomal instability. Mechanistically, YES1 sustained FOXM1 protein levels and elevated expression of FOXM1 target genes that control centrosome function and are essential for effective and accurate mitotic progression. In both in vitro and in vivo TNBC models, YES1 suppression potentiated the efficacy of taxanes, cornerstone drugs for TNBC that require elevated chromosomal instability for efficacy. Clinically, elevated expression of YES1 was associated with worse overall survival of patients with TNBC treated with taxane and anthracycline combination regimens. Together, this study demonstrates that YES1 is an essential regulator of genome stability in TNBC that can be leveraged to improve taxane efficacy. Significance: YES1 is a sentinel regulator of genomic maintenance that controls centrosome homeostasis and chromosome stability through FOXM1, revealing this pathway as a therapeutic vulnerability for enhancing taxane efficacy in triple-negative breast cancer.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"3556-3573"},"PeriodicalIF":12.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11534525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0