Cancer CellPub Date : 2024-10-24DOI: 10.1016/j.ccell.2024.10.002
Samuel N. Breit, David A. Brown, Vicky W.W. Tsai
{"title":"GDF15 research from bench to bedside","authors":"Samuel N. Breit, David A. Brown, Vicky W.W. Tsai","doi":"10.1016/j.ccell.2024.10.002","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.10.002","url":null,"abstract":"Pre-clinical data suggest that increased circulating growth differentiation factor 15 (GDF15) is a cause of both anorexia/cachexia syndromes and hyperemesis gravidarum in pregnancy, serious conditions with no highly effective treatment. A phase 2 study of a therapeutic GDF15 monoclonal antibody in the <em>New England Journal of Medicine</em> suggests that effective treatment of anorexia/cachexia in cancer may be approaching.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"8 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489054","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}
Cancer CellPub Date : 2024-10-24DOI: 10.1016/j.ccell.2024.10.003
Amber K. Hamilton, Alexander B. Radaoui, Matthew Tsang, Daniel Martinez, Karina L. Conkrite, Khushbu Patel, Simone Sidoli, Alberto Delaidelli, Apexa Modi, Jo Lynne Rokita, Maria V. Lane, Nicholas Hartnett, Raphael D. Lopez, Bo Zhang, Chuwei Zhong, Brian Ennis, Daniel P. Miller, Miguel A. Brown, Komal S. Rathi, Pichai Raman, Sharon J. Diskin
{"title":"A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma","authors":"Amber K. Hamilton, Alexander B. Radaoui, Matthew Tsang, Daniel Martinez, Karina L. Conkrite, Khushbu Patel, Simone Sidoli, Alberto Delaidelli, Apexa Modi, Jo Lynne Rokita, Maria V. Lane, Nicholas Hartnett, Raphael D. Lopez, Bo Zhang, Chuwei Zhong, Brian Ennis, Daniel P. Miller, Miguel A. Brown, Komal S. Rathi, Pichai Raman, Sharon J. Diskin","doi":"10.1016/j.ccell.2024.10.003","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.10.003","url":null,"abstract":"Cancer immunotherapies produce remarkable results in B cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor and normal tissues to identify biologically relevant cell surface immunotherapeutic targets for neuroblastoma, an often-fatal childhood cancer. Proteogenomic analyses reveal sixty high-confidence candidate immunotherapeutic targets, and we prioritize delta-like canonical notch ligand 1 (DLK1) for further study. High expression of DLK1 directly correlates with a super-enhancer. Immunofluorescence, flow cytometry, and immunohistochemistry show robust cell surface expression of DLK1. Short hairpin RNA mediated silencing of DLK1 in neuroblastoma cells results in increased cellular differentiation. ADCT-701, a DLK1-targeting antibody-drug conjugate (ADC), shows potent and specific cytotoxicity in DLK1-expressing neuroblastoma xenograft models. Since high DLK1 expression is found in several adult and pediatric cancers, our study demonstrates the utility of a proteogenomic approach and credentials DLK1 as an immunotherapeutic target.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"12 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488632","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}
{"title":"Overcoming tyrosine kinase inhibitor resistance in lung cancer brain metastasis with CTLA4 blockade","authors":"Minjie Fu, Jiaxu Zhao, Licheng Zhang, Zhewei Sheng, Xiaohui Li, Fufang Qiu, Yuan Feng, Muyuan You, Hao Xu, Jinsen Zhang, Rui Zeng, Yang Huang, Cheng Li, Wenhan Chen, Zheng Chen, Haibao Peng, Longzhi Li, Yonghe Wu, Dan Ye, Yudan Chi, Ying Mao","doi":"10.1016/j.ccell.2024.09.012","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.09.012","url":null,"abstract":"Lung cancer brain metastasis (LCBM) poses a significant clinical challenge due to acquired resistance to tyrosine kinase inhibitor (TKI) treatment. To elucidate its underlying mechanisms, we employed single-cell RNA sequencing analysis on surgically obtained LCBM samples with diverse genetic backgrounds and TKI treatment histories. Our study uncovers that TKI treatment elevates the immune checkpoint CTLA4 expression in T cells, promoting an immune-suppressive microenvironment. This immunomodulation is initiated by tumor-derived HMGB1 in response to TKIs. In LCBM syngeneic murine models with TKI-sensitive or TKI-resistant <em>EGFR</em> mutations, combining CTLA4 blockade with TKIs demonstrates enhanced efficacy over TKI monotherapy or TKIs with PD1 blockade. These findings provide insights into the TKI resistance mechanisms and highlight the potential of CTLA4 blockade in effectively overcoming TKI resistance in LCBM.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"6 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444125","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}
Cancer CellPub Date : 2024-10-17DOI: 10.1016/j.ccell.2024.09.015
Mingyong Liu, Bo Zhu, Qi-Jing Li
{"title":"IL-1 signaling in aging and cancer: An inflammaging feedback loop unveiled","authors":"Mingyong Liu, Bo Zhu, Qi-Jing Li","doi":"10.1016/j.ccell.2024.09.015","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.09.015","url":null,"abstract":"In a <em>Science</em> paper, Park et al. identified interleukin (IL)-1α as a key driver of positive feedback in inflammaging, linking aging-associated downregulation of DNMT3A to increased IL-1α production in lung myeloid cells. This triggers emergency myelopoiesis in the bone marrow, amplifying myeloid-mediated intratumoral immunosuppression for tumor progression in aged mice.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"14 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444129","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}
Cancer CellPub Date : 2024-10-17DOI: 10.1016/j.ccell.2024.09.014
William L. Hwang, Ella N. Perrault, Alexander Birbrair, Brandi J. Mattson, David H. Gutmann, Donald J. Mabbott, Edna Cukierman, Elizabeth A. Repasky, Erica K. Sloan, Hui Zong, Ihsan Ekin Demir, Jami L. Saloman, Jeremy C. Borniger, Jian Hu, Jorg Dietrich, Joshua J. Breunig, Kaan Çifcibaşı, Khalil Ali Ahmad Kasm, Manuel Valiente, Max Wintermark, Moran Amit
{"title":"Integrating priorities at the intersection of cancer and neuroscience","authors":"William L. Hwang, Ella N. Perrault, Alexander Birbrair, Brandi J. Mattson, David H. Gutmann, Donald J. Mabbott, Edna Cukierman, Elizabeth A. Repasky, Erica K. Sloan, Hui Zong, Ihsan Ekin Demir, Jami L. Saloman, Jeremy C. Borniger, Jian Hu, Jorg Dietrich, Joshua J. Breunig, Kaan Çifcibaşı, Khalil Ali Ahmad Kasm, Manuel Valiente, Max Wintermark, Moran Amit","doi":"10.1016/j.ccell.2024.09.014","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.09.014","url":null,"abstract":"Cancer neuroscience is a rapidly growing multidisciplinary field that conceptualizes tumors as tissues fully integrated into the nervous system. Recognizing the complexity and challenges in this field is of fundamental importance to achieving the goal of translational impact for cancer patients. Our commentary highlights key scientific priorities, optimal training settings, and roadblocks to translating scientific findings to the clinic in this emerging field, aiming to formulate a transformative and cohesive path forward.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"2 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444124","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}
Cancer CellPub Date : 2024-10-14DOI: 10.1016/j.ccell.2024.09.011
Evelyn Fitzsimons, Danwen Qian, Andrei Enica, Krupa Thakkar, Marcellus Augustine, Samuel Gamble, James L. Reading, Kevin Litchfield
{"title":"A pan-cancer single-cell RNA-seq atlas of intratumoral B cells","authors":"Evelyn Fitzsimons, Danwen Qian, Andrei Enica, Krupa Thakkar, Marcellus Augustine, Samuel Gamble, James L. Reading, Kevin Litchfield","doi":"10.1016/j.ccell.2024.09.011","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.09.011","url":null,"abstract":"Tumor-infiltrating B cells play a significant role in tumor development, progression, and prognosis, yet a comprehensive classification system is lacking. To address this gap, we present a pan-cancer single-cell RNA sequencing (scRNA-seq) atlas of tumor-infiltrating B and plasma cells across a large sample cohort. We identify key B cell subset signatures, revealing distinct subpopulations and highlighting the heterogeneity and functional diversity of these cells in the tumor microenvironment. We explore associations between B cell subsets and checkpoint inhibitor therapy responses, finding subset-specific effects on overall response. Additionally, we examine B and T cell crosstalk, identifying unique ligand-receptor pairs for specific B cell subsets, spatially validated. This comprehensive dataset serves as a valuable resource, providing a detailed atlas that enhances the understanding of B cell complexity in tumors and opens new avenues for research and therapeutic strategies.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"229 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431225","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}
{"title":"A prospective study of neoadjuvant pembrolizumab plus chemotherapy for resectable esophageal squamous cell carcinoma: The Keystone-001 trial","authors":"Xiaobin Shang, Yongjie Xie, Jinpu Yu, Chen Zhang, Gang Zhao, Fei Liang, Liang Liu, Weihong Zhang, Runmei Li, Wenwen Yu, Jie Yue, Chuangui Chen, Xiaofeng Duan, Zhao Ma, Zuoyu Chen, Yanjuan Xiong, Fan Yang, Jianyu Xiao, Rui Zhang, Pengpeng Liu, Hongjing Jiang","doi":"10.1016/j.ccell.2024.09.008","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.09.008","url":null,"abstract":"In this phase II study, 47 patients with locally advanced, resectable esophageal squamous cell carcinoma (ESCC) received three cycles of pembrolizumab plus chemotherapy, followed by Da Vinci robot-assisted surgery. The primary endpoints were safety and major pathological response (MPR). Key secondary endpoints included complete pathological response (pCR) and survival. No grade ≥3 adverse events or surgical delays occurred during neoadjuvant therapy. Among 46 patients studied for efficacy, the MPR and pCR rates were 72% and 41%, respectively. After a median follow-up of 27.2 months, the 2-year overall survival (OS) and disease-free survival (DFS) rates were 91% and 89%, respectively. Expansion of TRGC2<sup>+</sup> NKT cells in peripheral blood correlated with neoadjuvant treatment effectiveness, which was validated by <em>in vitro</em> organoid experiments and external cancer datasets, and its functional classification and mechanism of action were further explored. These findings show preoperative pembrolizumab plus chemotherapy is a promising therapeutic strategy for resectable ESCC.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"29 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431224","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}
Cancer CellPub Date : 2024-10-14DOI: 10.1016/j.ccell.2024.09.013
Colleen Sturdevant, Yuliya Pylayeva-Gupta
{"title":"B cell heterogeneity in cancer comes of age","authors":"Colleen Sturdevant, Yuliya Pylayeva-Gupta","doi":"10.1016/j.ccell.2024.09.013","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.09.013","url":null,"abstract":"The role of B cells in cancer remains incompletely understood. Three recent publications, including a study by Fitzsimons et al. in this issue of <em>Cancer Cell</em>,<span><span><sup>1</sup></span></span> use single-cell RNA sequencing to define pan-cancer atlases of tumor-infiltrating B cell subsets, paving the way for profound advances in our understanding of B cell-dependent antitumor immunity.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"9 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431226","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}
Cancer CellPub Date : 2024-10-10DOI: 10.1016/j.ccell.2024.09.010
Claudia Galassi, Timothy A. Chan, Ilio Vitale, Lorenzo Galluzzi
{"title":"The hallmarks of cancer immune evasion","authors":"Claudia Galassi, Timothy A. Chan, Ilio Vitale, Lorenzo Galluzzi","doi":"10.1016/j.ccell.2024.09.010","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.09.010","url":null,"abstract":"According to the widely accepted “three Es” model, the host immune system <u>e</u>liminates malignant cell precursors and contains microscopic neoplasms in a dynamic <u>e</u>quilibrium, preventing cancer outgrowth until neoplastic cells acquire genetic or epigenetic alterations that enable immune <u>e</u>scape. This immunoevasive phenotype originates from various mechanisms that can be classified under a novel “three Cs” conceptual framework: (1) <u>c</u>amouflage, which hides cancer cells from immune recognition, (2) <u>c</u>oercion, which directly or indirectly interferes with immune effector cells, and (3) <u>c</u>ytoprotection, which shields malignant cells from immune cytotoxicity. Blocking the ability of neoplastic cells to evade the host immune system is crucial for increasing the efficacy of modern immunotherapy and conventional therapeutic strategies that ultimately activate anticancer immunosurveillance. Here, we review key hallmarks of cancer immune evasion under the “three Cs” framework and discuss promising strategies targeting such immunoevasive mechanisms.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"62 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142398286","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}
Cancer CellPub Date : 2024-10-10DOI: 10.1016/j.ccell.2024.09.009
Rei Kudo, Anton Safonov, Catherine Jones, Enrico Moiso, Jonathan R. Dry, Hong Shao, Sharanya Nag, Edaise M. da Silva, Selma Yeni Yildirim, Qing Li, Elizabeth O'Connell, Payal Patel, Marie Will, Atsushi Fushimi, Marimar Benitez, Martina Bradic, Li Fan, Harikrishna Nakshatri, Dhivya R. Sudhan, Christopher R. Denz, Sarat Chandarlapaty
{"title":"Long-term breast cancer response to CDK4/6 inhibition defined by TP53-mediated geroconversion","authors":"Rei Kudo, Anton Safonov, Catherine Jones, Enrico Moiso, Jonathan R. Dry, Hong Shao, Sharanya Nag, Edaise M. da Silva, Selma Yeni Yildirim, Qing Li, Elizabeth O'Connell, Payal Patel, Marie Will, Atsushi Fushimi, Marimar Benitez, Martina Bradic, Li Fan, Harikrishna Nakshatri, Dhivya R. Sudhan, Christopher R. Denz, Sarat Chandarlapaty","doi":"10.1016/j.ccell.2024.09.009","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.09.009","url":null,"abstract":"Inhibition of CDK4/6 kinases has led to improved outcomes in breast cancer. Nevertheless, only a minority of patients experience long-term disease control. Using a large, clinically annotated cohort of patients with metastatic hormone receptor-positive (HR+) breast cancer, we identify <em>TP53</em> loss (27.6%) and <em>MDM2</em> amplification (6.4%) to be associated with lack of long-term disease control. Human breast cancer models reveal that p53 loss does not alter CDK4/6 activity or G1 blockade but instead promotes drug-insensitive p130 phosphorylation by CDK2. The persistence of phospho-p130 prevents DREAM complex assembly, enabling cell-cycle re-entry and tumor progression. Inhibitors of CDK2 can overcome p53 loss, leading to geroconversion and manifestation of senescence phenotypes. Complete inhibition of both CDK4/6 and CDK2 kinases appears to be necessary to facilitate long-term response across genomically diverse HR+ breast cancers.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"8 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142398281","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}
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