Cancer research最新文献

Correction: Comprehensive DNA Methylation Analysis Indicates That Pancreatic Intraepithelial Neoplasia Lesions Are Acinar-Derived and Epigenetically Primed for Carcinogenesis.

IF 12.5 1区医学

Cancer research Pub Date : 2025-04-03 DOI: 10.1158/0008-5472.CAN-25-0652

Emily K W Lo, Brian M Mears, H Carlo Maurer, Adrian Idrizi, Kasper D Hansen, Elizabeth D Thompson, Laura D Wood, Ralph H Hruban, Kenneth P Olive, Andrew P Feinberg

引用次数: 0

Editor's Note: TRIM59 Promotes Gliomagenesis by Inhibiting TC45 Dephosphorylation of STAT3.

IF 12.5 1区医学

Cancer research Pub Date : 2025-04-03 DOI: 10.1158/0008-5472.CAN-25-0798

Youzhou Sang, Yanxin Li, Lina Song, Angel A Alvarez, Weiwei Zhang, Deguan Lv, Jianming Tang, Feng Liu, Zhijie Chang, Shigetsugu Hatakeyama, Bo Hu, Shi-Yuan Cheng, Haizhong Feng

引用次数: 0

Targeting ARPC1B Overcomes Immune Checkpoint Inhibitor Resistance in Glioblastoma by Reversing Protumorigenic Macrophage Polarization. 靶向ARPC1B通过逆转致瘤前巨噬细胞极化克服胶质母细胞瘤免疫检查点抑制剂耐药性

IF 12.5 1区医学

Cancer research Pub Date : 2025-04-03 DOI: 10.1158/0008-5472.CAN-24-2286

Tianqi Liu, Tao Sun, Xin Chen, Jianqi Wu, Xiaoqian Sun, Xing Liu, Haixu Yan, Qiang Fu, Zirong Fan, Xiangyu Wang, Peng Cheng, Wen Cheng, Anhua Wu

{"title":"Targeting ARPC1B Overcomes Immune Checkpoint Inhibitor Resistance in Glioblastoma by Reversing Protumorigenic Macrophage Polarization.","authors":"Tianqi Liu, Tao Sun, Xin Chen, Jianqi Wu, Xiaoqian Sun, Xing Liu, Haixu Yan, Qiang Fu, Zirong Fan, Xiangyu Wang, Peng Cheng, Wen Cheng, Anhua Wu","doi":"10.1158/0008-5472.CAN-24-2286","DOIUrl":"10.1158/0008-5472.CAN-24-2286","url":null,"abstract":"Immunotherapy has elicited significant improvements in outcomes for patients with several tumor types. However, the immunosuppressive microenvironment in glioblastoma (GBM) restricts the therapeutic efficacy of immune checkpoint blockade (ICB). In this study, we investigated the components of the immune microenvironment that contribute to ICB failure in GBM to elucidate the underlying causes of immunotherapeutic resistance. Macrophages were identified as a main contributor to ICB resistance. Expression of actin-related protein 2/3 complex subunit 1B (ARPC1B), a regulatory subunit of the Arp2/3 complex, was elevated in GBM and correlated with macrophage enrichment and prognosis. ARPC1B in tumor cells increased STAT1 expression and subsequent IL10 production, which induced a protumorigenic macrophage state. Mechanistically, ARPC1B inhibited the ubiquitination and degradation of STAT1 by preventing the E3 ubiquitin ligase NEDD4L from binding to STAT1 and by supporting the interaction between STAT1 and the deubiquitinase USP7. Inhibiting ARPC1B reshaped the immunosuppressive microenvironment and increased the efficacy of ICB in GBM models. This study highlights the important role of ARPC1B in macrophage-mediated immunosuppression and proposes a combination treatment regimen for GBM immunotherapy. Significance: ARPC1B induces macrophage-mediated immunosuppression by activating a STAT1/IL10 axis and can be targeted to improve the efficacy of immune checkpoint blockade in glioblastoma.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"1236-1252"},"PeriodicalIF":12.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000884","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

Tumor Suppressors Condition Differential Responses to the Selective CDK2 Inhibitor BLU-222.

IF 12.5 1区医学

Cancer research Pub Date : 2025-04-03 DOI: 10.1158/0008-5472.CAN-24-2244

Adam P Dommer, Vishnu Kumarasamy, Jianxin Wang, Thomas N O'Connor, Michelle Roti, Sidney Mahan, Karen McLean, Erik S Knudsen, Agnieszka K Witkiewicz

{"title":"Tumor Suppressors Condition Differential Responses to the Selective CDK2 Inhibitor BLU-222.","authors":"Adam P Dommer, Vishnu Kumarasamy, Jianxin Wang, Thomas N O'Connor, Michelle Roti, Sidney Mahan, Karen McLean, Erik S Knudsen, Agnieszka K Witkiewicz","doi":"10.1158/0008-5472.CAN-24-2244","DOIUrl":"10.1158/0008-5472.CAN-24-2244","url":null,"abstract":"Cyclin-dependent kinase 2 (CDK2) inhibitors have recently been developed and have entered clinical trials. Combination approaches can help broaden the use of therapeutic agents and establish more effective treatments. Here, we evaluated the selective CDK2 inhibitor BLU-222 for mechanisms of response in the context of ovarian and breast cancer models. Sensors of cellular CDK activity indicated that sensitivity to either CDK4/6 or CDK2 inhibition was related to the differential dependence on a single CDK for G1-S transition. Unlike CDK4/6 inhibitors, BLU-222 was able to robustly inhibit proliferation through cell-cycle inhibition in both G1 and G2 phases. However, it remained possible for cells to reenter the cell cycle upon drug withdrawal. The antiproliferative strength and impact on G1-S versus G2-M accumulation was mediated by the RB tumor suppressor. To broaden the sensitivity to CDK2 inhibition, combinatorial drug screens were performed that identified both synergistic (e.g., CDK4/6 inhibitors) and antagonistic (e.g., WEE1 inhibitors) relationships. Models that were exceptionally sensitive to CDK2 inhibition displayed coordinate expression of cyclin E1 and P16INK4A, an endogenous CDK4/6 inhibitor. Functional studies demonstrated that P16INK4A and CDK4/6 activity were key mediators of sensitivity to BLU-222. Clinical gene and protein expression analyses revealed a positive correlation between cyclin E1 and P16INK4A and identified that ∼25% of ovarian cancers exhibited coordinate expression of cyclin E, P16INK4A, and RB, indicative of strong sensitivity to CDK2 inhibition. Together, this work advances a precision strategy for the use of CDK2 inhibitors in the context of ovarian and breast cancers. Significance: The CDK2-specific inhibitor BLU-222 shows preclinical efficacy in breast and ovarian cancer with select determinants of response and holds promise in combinatorial strategies. See related article by House and colleagues, p. 1297.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"1310-1326"},"PeriodicalIF":12.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405738","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

Profiling the Activity of the Potent and Highly Selective CDK2 Inhibitor BLU-222 Reveals Determinants of Response in CCNE1-Aberrant Ovarian and Endometrial Tumors.

IF 12.5 1区医学

Cancer research Pub Date : 2025-04-03 DOI: 10.1158/0008-5472.CAN-24-2360

Nealia C House, Victoria E Brown, Maxine Chen, Liang Yuan, Sydney L Moore, Jian Guo, Yoon Jong Choi, Lakshmi Muthuswamy, Scott Ribich, Philip Ramsden, Kerrie L Faia

{"title":"Profiling the Activity of the Potent and Highly Selective CDK2 Inhibitor BLU-222 Reveals Determinants of Response in CCNE1-Aberrant Ovarian and Endometrial Tumors.","authors":"Nealia C House, Victoria E Brown, Maxine Chen, Liang Yuan, Sydney L Moore, Jian Guo, Yoon Jong Choi, Lakshmi Muthuswamy, Scott Ribich, Philip Ramsden, Kerrie L Faia","doi":"10.1158/0008-5472.CAN-24-2360","DOIUrl":"10.1158/0008-5472.CAN-24-2360","url":null,"abstract":"BLU-222 is an investigational, potent, highly selective, orally bioavailable cyclin-dependent kinase 2 (CDK2) inhibitor in clinical development. BLU-222 demonstrated robust antitumor activity in select CCNE1-high ovarian and endometrial cancer models. We used a combination of CRISPR whole-genome screens coupled with targeted genetic and pharmacologic approaches in ovarian and endometrial cell lines to identify biological determinants to predict BLU-222 monotherapy activity. Rb and p16 expression were biomarkers that enriched for CDK2-dependency/BLU-222 sensitivity in CCNE1-overexpressed, nonamplified cells. Furthermore, intact Rb and low p16 expression predicted a BLU-222 and CDK4/6 inhibitor combination response. BLU-222 demonstrated robust activity in combination with carboplatin or paclitaxel in CCNE1-aberrant models, rendering chemotherapy-resistant tumors strongly sensitive to the combination. These findings demonstrate that response to CDK2 inhibition by BLU-222 can be further predicted using a combinatorial biomarker signature that could refine patient selection criteria in CCNE1-high patients and support clinical development. Significance: The identification of biomarkers of response to the CDK2-selective inhibitor BLU-222 and effective combinations with CDK4/6 inhibitors or chemotherapy could enable precision medicine strategies for CDK2 inhibition in ovarian and endometrial cancer. See related article by Dommer and colleagues, p. 1310.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"1297-1309"},"PeriodicalIF":12.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967718/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405735","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

Transforming Cancer Therapy: Unlocking the Potential of Targeting Vascular and Stromal Cells in the Tumor Microenvironment

IF 11.2 1区医学

Cancer research Pub Date : 2025-04-02 DOI: 10.1158/0008-5472.can-24-4744

Lu Liu, Yuheng Zhang, Hanyu Liu, Jian Yang, Qi Tian, Nareekarn Chueakula, Saravana Ramasamy, Navin Kumar Verma, Christine Cheung, Anjali P. Kusumbe

引用次数: 0

Spatial Profiling Identifies Regionally Distinct Microenvironments and Targetable Immunosuppressive Mechanisms in Pediatric Osteosarcoma Pulmonary Metastases.

IF 12.5 1区医学

Cancer research Pub Date : 2025-04-02 DOI: 10.1158/0008-5472.CAN-24-3723

Jason Eigenbrood, Nathan Wong, Paul Mallory, Janice S Pereira, Demond Williams, Douglass W Morris-Ii, Jessica A Beck, James C Cronk, Carly M Sayers, Monica Mendez, Linus Kaiser, Julie Galindo, Jatinder Singh, Ashley Cardamone, Milind Pore, Michael Kelly, Amy K LeBlanc, Jennifer Cotter, Rosandra N Kaplan, Troy A McEachron

{"title":"Spatial Profiling Identifies Regionally Distinct Microenvironments and Targetable Immunosuppressive Mechanisms in Pediatric Osteosarcoma Pulmonary Metastases.","authors":"Jason Eigenbrood, Nathan Wong, Paul Mallory, Janice S Pereira, Demond Williams, Douglass W Morris-Ii, Jessica A Beck, James C Cronk, Carly M Sayers, Monica Mendez, Linus Kaiser, Julie Galindo, Jatinder Singh, Ashley Cardamone, Milind Pore, Michael Kelly, Amy K LeBlanc, Jennifer Cotter, Rosandra N Kaplan, Troy A McEachron","doi":"10.1158/0008-5472.CAN-24-3723","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-3723","url":null,"abstract":"Osteosarcoma is the most common malignant bone tumor in young patients and remains a significant clinical challenge, particularly at the metastatic stage. Studies detailing the immunosuppressive mechanisms within the metastatic osteosarcoma microenvironment are needed to elucidate the cellular communities in the metastatic microenvironment that support metastatic growth and to identify therapeutic approaches to target the crosstalk between cancer cells and the microenvironment. Here, we performed spatial transcriptional profiling on a cohort of osteosarcoma pulmonary metastases from pediatric patients. The data revealed a conserved spatial gene expression pattern resembling a foreign body granuloma, characterized by peripheral inflammatory signaling, fibrocollagenous encapsulation, lymphocyte exclusion, and peritumoral macrophage accumulation. The intratumoral microenvironment of these lesions, however, lacked inflammatory signaling. Exploration of spatially distinct drug-gene interactions identified the CXCR4 signaling axis, which displayed spatial heterogeneity and complexity, as a potential therapeutic target that bridges both the intratumoral and extratumoral microenvironments. Collectively, this study reveals that metastatic osteosarcoma is comprised of multiple regionally distinct immunosuppressive microenvironments.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771215","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

FGFR2 Abrogation Intercepts Pancreatic Ductal Adenocarcinoma Development

IF 11.2 1区医学

Cancer research Pub Date : 2025-04-02 DOI: 10.1158/0008-5472.can-24-4576

Claudia Tonelli, Astrid Deschênes, Victoria A. Gaeth, Amanda Jensen, Nandan Vithlani, Melissa A. Yao, Zhen Zhao, Youngkyu Park, David A. Tuveson

{"title":"FGFR2 Abrogation Intercepts Pancreatic Ductal Adenocarcinoma Development","authors":"Claudia Tonelli, Astrid Deschênes, Victoria A. Gaeth, Amanda Jensen, Nandan Vithlani, Melissa A. Yao, Zhen Zhao, Youngkyu Park, David A. Tuveson","doi":"10.1158/0008-5472.can-24-4576","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-4576","url":null,"abstract":"Activating KRAS mutations are a key feature of pancreatic ductal adenocarcinoma (PDA) and drive tumor initiation and progression. However, mutant KRAS by itself is weakly oncogenic. Defining the pathways that cooperate with mutant KRAS to induce tumorigenesis could identify prevention and treatment strategies. Analyzing organoids and murine and human pancreatic specimens, we found that the receptor tyrosine kinase FGFR2 was progressively up-regulated in mutant KRAS-driven metaplasia, pre-cancerous lesions and classical PDA. In genetic mouse models, FGFR2 inactivation impeded mutant KRAS-driven transformation of acinar cells by reducing proliferation and MAPK pathway activation. FGFR2 abrogation significantly delayed tumor formation and extended the survival of these mice. Furthermore, FGFR2 collaborated with EGFR and dual blockade of these receptor signaling pathways significantly reduced mutant KRAS-induced pre-cancerous lesion formation. Together, these data have uncovered a pivotal role for FGFR2 in the early phases of pancreatic tumorigenesis, paving the way for future therapeutic applications of FGFR2 inhibitors for pancreatic cancer interception.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"103 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757890","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

The Prolonged Half-Life of the p53 Missense Variant R248Q Promotes Accumulation and Heterotetramer Formation with Wildtype p53 to Exert the Dominant-Negative Effect

IF 11.2 1区医学

Cancer research Pub Date : 2025-03-31 DOI: 10.1158/0008-5472.can-24-1136

Nancy Klemm, Roman R. Schimmer, Nils K. Konrad, Flavian Thelen, Jonas Fullin, Ebru Topçu, Christian Koch, Milena Treacy, Matthew Joseph. Leventhal, Marco M. Bühler, Veronika Lysenko, Alexandre P. A. Theocharides, Kari J. Kurppa, Stefan Balabanov, Tuncay Baubec, Andrei V. Krivtsov, Peter G. Miller, Scott A. Armstrong, Benjamin L. Ebert, Markus G. Manz, Cesar Nombela-Arrieta, Steffen Boettcher

{"title":"The Prolonged Half-Life of the p53 Missense Variant R248Q Promotes Accumulation and Heterotetramer Formation with Wildtype p53 to Exert the Dominant-Negative Effect","authors":"Nancy Klemm, Roman R. Schimmer, Nils K. Konrad, Flavian Thelen, Jonas Fullin, Ebru Topçu, Christian Koch, Milena Treacy, Matthew Joseph. Leventhal, Marco M. Bühler, Veronika Lysenko, Alexandre P. A. Theocharides, Kari J. Kurppa, Stefan Balabanov, Tuncay Baubec, Andrei V. Krivtsov, Peter G. Miller, Scott A. Armstrong, Benjamin L. Ebert, Markus G. Manz, Cesar Nombela-Arrieta, Steffen Boettcher","doi":"10.1158/0008-5472.can-24-1136","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1136","url":null,"abstract":"Missense mutants of p53 - such as the frequent hotspot variant R248Q - exert a dominant-negative effect (DNE) on wildtype (WT) p53 in cancer cells with monoallelic TP53 mutations. However, the precise functional and molecular mechanisms of the DNE have remained elusive due to a lack of appropriate model systems. Here, we developed a variety of model systems, including CRISPR-edited human isogenic cell lines and transcriptional reporter cell lines, and targeted protein degradation assays that were combined with functional and molecular analyses to functionally characterize the DNE. Formation of heterotetramers between R248Q and WT p53 impaired proper WT p53 functionality by preventing DNA binding and subsequent target gene transactivation. Furthermore, the markedly increased protein half-life of R248Q led to supraphysiologic levels of R248Q, which was critically required for the DNE. Drug-induced targeted protein degradation of R248Q to lower the R248Q:WT ratio restored the transcriptional activity of WT p53, induced anti-proliferative effects in cancer cells in vitro, and elicited strong therapeutic activity in vivo. Together, this study provides mechanistic insights into the DNE of p53 missense mutants and indicates that the DNE represents a promising therapeutic target.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"36 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744985","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

PROX1: a key regulator of hepatocyte identity and tumorigenesis

IF 11.2 1区医学

Cancer research Pub Date : 2025-03-31 DOI: 10.1158/0008-5472.can-25-1377

Terence Kin Wah. Lee, Stephanie Ma

{"title":"PROX1: a key regulator of hepatocyte identity and tumorigenesis","authors":"Terence Kin Wah. Lee, Stephanie Ma","doi":"10.1158/0008-5472.can-25-1377","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-1377","url":null,"abstract":"During ontogeny, the modulation of cell fate plasticity in stem cells is meticulously controlled as they undergo differentiation into distinct cell lineages. Dysregulation of this plasticity can result in pathological conditions, such as oncogenesis. Transcription factors are pivotal in orchestrating this cellular transition by initiating gene expression programs that define cell identity. Notably, the investigation of transcriptional repressors has garnered significant attention in elucidating the susceptibility of cancer development. A recent research article published in Nature Genetics unveiled the identification of a liver-specific protein, named PROX1, which maintains cellular identity and impedes the initiation and advancement of liver cancer. Analysis of liver cancer patient specimens demonstrated a positive association between elevated levels of PROX1 and improved prognosis as well as extended survival. Utilizing various liver cancer mouse models, the researchers demonstrated that PROX1 can impede tumor initiation and decelerate cancer progression. This study offers valuable insights for potential therapeutic interventions and introduces novel opportunities for investigating \"safeguard repressors\" in diverse tissue types.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"33 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744986","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