Cancer discovery最新文献

{"title":"Chromothripsis-Mediated Small Cell Lung Carcinoma.","authors":"Natasha Rekhtman, Sam E Tischfield, Christopher A Febres-Aldana, Jake June-Koo Lee, Jason C Chang, Benjamin O Herzberg, Pier Selenica, Hyung Jun Woo, Chad M Vanderbilt, Soo-Ryum Yang, Fei Xu, Anita S Bowman, Edaise M da Silva, Anne Marie Noronha, Diana L Mandelker, Miika Mehine, Semanti Mukherjee, Juan Blanco-Heredia, John J Orgera, Gouri J Nanjangud, Marina K Baine, Rania G Aly, Jennifer L Sauter, William D Travis, Omid Savari, Andre L Moreira, Christina J Falcon, Francis M Bodd, Christina E Wilson, Jacklynn V Sienty, Parvathy Manoj, Harsha Sridhar, Lu Wang, Noura J Choudhury, Michael Offin, Helena A Yu, Alvaro Quintanal-Villalonga, Michael F Berger, Marc Ladanyi, Mark T A Donoghue, Jorge S Reis-Filho, Charles M Rudin","doi":"10.1158/2159-8290.CD-24-0286","DOIUrl":"10.1158/2159-8290.CD-24-0286","url":null,"abstract":"<p><p>Small cell lung carcinoma (SCLC) is a highly aggressive malignancy that is typically associated with tobacco exposure and inactivation of RB1 and TP53 genes. Here, we performed detailed clinicopathologic, genomic, and transcriptomic profiling of an atypical subset of SCLC that lacked RB1 and TP53 co-inactivation and arose in never/light smokers. We found that most cases were associated with chromothripsis-massive, localized chromosome shattering-recurrently involving chromosome 11 or 12 and resulting in extrachromosomal amplification of CCND1 or co-amplification of CCND2/CDK4/MDM2, respectively. Uniquely, these clinically aggressive tumors exhibited genomic and pathologic links to pulmonary carcinoids, suggesting a previously uncharacterized mode of SCLC pathogenesis via transformation from lower-grade neuroendocrine tumors or their progenitors. Conversely, SCLC in never-smokers harboring inactivated RB1 and TP53 exhibited hallmarks of adenocarcinoma-to-SCLC derivation, supporting two distinct pathways of plasticity-mediated pathogenesis of SCLC in never-smokers. Significance: Here, we provide the first detailed description of a unique SCLC subset lacking RB1/TP53 alterations and identify extensive chromothripsis and pathogenetic links to pulmonary carcinoids as its hallmark features. This work defines atypical SCLC as a novel entity among lung cancers, highlighting its exceptional histogenesis, clinicopathologic characteristics, and therapeutic vulnerabilities. See related commentary by Nadeem and Drapkin, p. 8.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"83-104"},"PeriodicalIF":29.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055042","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}

{"title":"Combined KRAS Inhibition and Immune Therapy Generates Durable Complete Responses in an Autochthonous PDAC Model.","authors":"Yonghong Liu, Jincheng Han, Wen-Hao Hsu, Kyle A LaBella, Pingna Deng, Xiaoying Shang, Paulino Tallón de Lara, Li Cai, Shan Jiang, Ronald A DePinho","doi":"10.1158/2159-8290.CD-24-0489","DOIUrl":"10.1158/2159-8290.CD-24-0489","url":null,"abstract":"<p><strong>Significance: </strong>Clinically available KRAS* inhibitors and IO agents alleviated the immunosuppressive tumor microenvironment in PDAC. Profound tumor regression and prolonged survival in an autochthonous PDAC model provide a compelling rationale for combining KRAS* inhibition with IO agents targeting multiple arms of the immunity cycle to combat PDAC.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"162-178"},"PeriodicalIF":29.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11858029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342164","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}

{"title":"Taking a Swing at TIMP1-Armed Immunosuppressive Astrocytes Unleashes T cell Immunity against Brain Metastases","authors":"Mihaela Lorger, Fiona James","doi":"10.1158/2159-8290.cd-24-1495","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1495","url":null,"abstract":"Summary: Priego and colleagues identify a secreted glycoprotein TIMP1, expressed downstream of the transcription factor STAT3, in a subpopulation of STAT3+ reactive astrocytes as a mediator of immunosuppression in late-stage brain metastases. The STAT3 inhibitor silibinin enhances the preclinical efficacy of the combined PD-1/CTLA4 immune checkpoint blockade, providing a rationale to translate the combination therapy into clinical use for this underserved patient group with poor prognosis. See related article by Priego et al., p. 179","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"16 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968214","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":"Implementing Mutational Epidemiology on a Global Scale: Lessons from Mutographs","authors":"Michael R. Stratton, Laura Humphreys, Ludmil B. Alexandrov, Allan Balmain, Paul Brennan, Peter J. Campbell, David H. Phillips","doi":"10.1158/2159-8290.cd-24-1687","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1687","url":null,"abstract":"Summary: The Mutographs Cancer Grand Challenge team aimed to discover unknown causes of cancer through mutational epidemiology, an alliance of cancer epidemiology and somatic genomics. By generating whole-genome sequences from thousands of cancers and normal tissues from more than 30 countries on five continents, it discovered unsuspected mutagenic exposures affecting millions of people, raised the possibility that some carcinogens act by altering forces of selection in tissue microenvironments rather than by mutagenesis, and demonstrated changes to the direction of somatic evolution in normal cells of the human body in response to exogenous exposures and noncancer diseases. See related article by Bressan et al., p. 16 See related article by Bhattacharjee et al., p. 28 See related article by Goodwin et al., p. 34","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"26 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968213","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":"Peto’s Paradox Is Dead. Long Live Peto’s Paradox","authors":"Michael J. Metzger","doi":"10.1158/2159-8290.cd-24-1539","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1539","url":null,"abstract":"Summary: In this issue, Compton and colleagues report the prevalence of neoplasia and malignant cancer in 292 species, based on 16,049 necropsy records, shedding light on susceptibility to cancer and the evolution of mechanisms that protect against cancer across a broad array of vertebrates. See related article by Compton et al., p. 227","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"49 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968215","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":"TIMP1 Mediates Astrocyte-Dependent Local Immunosuppression in Brain Metastasis Acting on Infiltrating CD8+ T Cells.","authors":"Neibla Priego, Ana de Pablos-Aragoneses, María Perea-García, Valentina Pieri, Carolina Hernández-Oliver, Laura Álvaro-Espinosa, Andrea Rojas, Oliva Sánchez, Ariane Steindl, Eduardo Caleiras, Fernando García, Santiago García-Martín, Osvaldo Graña-Castro, Sandra García-Mulero, Diego Serrano, Paloma Velasco-Beltrán, Borja Jiménez-Lasheras, Leire Egia-Mendikute, Luise Rupp, Antonia Stammberger, Matthias Meinhardt, Anas Chaachou-Charradi, Elena Martínez-Saez, Luca Bertero, Paola Cassoni, Luca Mangherini, Alessia Pellerino, Roberta Rudà, Riccardo Soffietti, Fatima Al-Shahrour, Paul Saftig, Rebeca Sanz-Pamplona, Marc Schmitz, Stephen J Crocker, Alfonso Calvo, Asís Palazón, Manuel Valiente","doi":"10.1158/2159-8290.CD-24-0134","DOIUrl":"10.1158/2159-8290.CD-24-0134","url":null,"abstract":"<p><p>Immunotherapies against brain metastases have shown clinical benefits when applied to asymptomatic patients, but they are largely ineffective in symptomatic cases for unknown reasons. Here, we dissect the heterogeneity in metastasis-associated astrocytes using single-cell RNA sequencing and report a population that blocks the antitumoral activity of infiltrating T cells. This protumoral activity is mediated by the secretion of tissue inhibitor of metalloproteinase-1 (TIMP1) from a cluster of pSTAT3+ astrocytes that acts on CD63+ CD8+ T cells to modulate their function. Using genetic and pharmacologic approaches in mouse and human brain metastasis models, we demonstrate that combining immune checkpoint blockade antibodies with the inhibition of astrocyte-mediated local immunosuppression may benefit patients with symptomatic brain metastases. We further reveal that the presence of tissue inhibitor of metalloproteinase-1 in liquid biopsies provides a biomarker to select patients for this combined immunotherapy. Overall, our findings demonstrate an unexpected immunomodulatory role for astrocytes in brain metastases with clinical implications. Significance: This study presents a significant advancement in understanding immune modulation in brain tumors and offers new insights into the potential therapeutic interventions for brain metastases. See related commentary by Lorger and James, p. 11.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"179-201"},"PeriodicalIF":29.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726018/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142361163","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}

{"title":"Cancer Neuroscience of Brain Tumors: From Multicellular Networks to Neuroscience-Instructed Cancer Therapies","authors":"Varun Venkataramani, Yvonne Yang, Sebastian Ille, Bogdana Suchorska, Sonja Loges, Heike Tost, Felix Sahm, Stefan M. Pfister, Andreas Trumpp, Sandro M. Krieg, Thomas Kuner, Wolfgang Wick, Frank Winkler","doi":"10.1158/2159-8290.cd-24-0194","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0194","url":null,"abstract":"Deepening our understanding of neuro-cancer interactions can innovate brain tumor treatment. This mini review unfolds the most relevant and recent insights into the neural mechanisms contributing to brain tumor initiation, progression, and resistance, including synaptic connections between neurons and cancer cells, paracrine neuro-cancer signaling, and cancer cells’ intrinsic neural properties. We explain the basic and clinical–translational relevance of these findings, identify unresolved questions and particularly interesting future research avenues, such as central nervous system neuro-immunooncology, and discuss the potential transferability to extracranial cancers. Lastly, we conceptualize ways toward clinical trials and develop a roadmap toward neuroscience-instructed brain tumor therapies. Significance: Neural influences on brain tumors drive their growth and invasion. Herein, we develop a roadmap to use these fundamentally new insights into brain tumor biology for improved outcomes.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"40 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968216","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":"Tracking non-genetic evolution from primary to metastatic ccRCC: TRACERx Renal","authors":"Ángel Fernández-Sanromán, Annika Fendler, Benjy J.Y. Tan, Anne-Laure Cattin, Charlotte Spencer, Rachael Thompson, Lewis Au, Irene Lobon, Husayn Ahmed. Pallikonda, Alice Martin, Fiona Byrne, Antonia Franz, Anna Mikolajczak, Haseeb Rahman, Zayd Tippu, Scott T.C. Shepherd, Hugang Feng, Daqi Deng, Andrew Rowan, Lisa Pickering, Andrew J.S. Furness, Kate Young, David Nicol, Sarah Maria. Rudman, Tim O'Brien, Kim Edmonds, Ashish Chandra, Steve Hazell, Kevin Litchfield, George Kassiotis, James Larkin, Samra Turajlic","doi":"10.1158/2159-8290.cd-24-0499","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0499","url":null,"abstract":"While the key aspects of genetic evolution and their clinical implications in clear cell renal-cell carcinoma (ccRCC) are well-documented, how genetic features co-evolve with the phenotype and tumor microenvironment (TME) remains elusive. Here, through joint genomic-transcriptomic analysis of 243 samples from 79 patients recruited to the TRACERx Renal study, we identify pervasive non-genetic intratumor heterogeneity, with over 40% not attributable to genetic alterations. By integrating tumor transcriptomes and phylogenetic structures, we observe convergent evolution to specific phenotypic traits, including cell proliferation, metabolic reprogramming and overexpression of putative cGAS-STING repressors amid high aneuploidy. We also uncover a co-evolution between the tumor and the T cell repertoire, as well as a longitudinal shift in the TME from an anti-tumor to an immunosuppressive state, linked to the acquisition of recurrently late ccRCC drivers 9p loss and SETD2 mutations. Our study reveals clinically-relevant and hitherto underappreciated non-genetic evolution patterns in ccRCC","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"1 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936175","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":"Tracking non-genetic evolution from primary to metastatic ccRCC: TRACERx Renal.","authors":"Ángel Fernández-Sanromán, Annika Fendler, Benjy J Y Tan, Anne-Laure Cattin, Charlotte Spencer, Rachael Thompson, Lewis Au, Irene Lobon, Husayn Ahmed Pallikonda, Alice Martin, Fiona Byrne, Antonia Franz, Anna Mikolajczak, Haseeb Rahman, Zayd Tippu, Scott T C Shepherd, Hugang Feng, Daqi Deng, Andrew Rowan, Lisa Pickering, Andrew J S Furness, Kate Young, David Nicol, Sarah Maria Rudman, Tim O'Brien, Kim Edmonds, Ashish Chandra, Steve Hazell, Kevin Litchfield, George Kassiotis, James Larkin, Samra Turajlic","doi":"10.1158/2159-8290.CD-24-0499","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0499","url":null,"abstract":"<p><p>While the key aspects of genetic evolution and their clinical implications in clear cell renal-cell carcinoma (ccRCC) are well-documented, how genetic features co-evolve with the phenotype and tumor microenvironment (TME) remains elusive. Here, through joint genomic-transcriptomic analysis of 243 samples from 79 patients recruited to the TRACERx Renal study, we identify pervasive non-genetic intratumor heterogeneity, with over 40% not attributable to genetic alterations. By integrating tumor transcriptomes and phylogenetic structures, we observe convergent evolution to specific phenotypic traits, including cell proliferation, metabolic reprogramming and overexpression of putative cGAS-STING repressors amid high aneuploidy. We also uncover a co-evolution between the tumor and the T cell repertoire, as well as a longitudinal shift in the TME from an anti-tumor to an immunosuppressive state, linked to the acquisition of recurrently late ccRCC drivers 9p loss and SETD2 mutations. Our study reveals clinically-relevant and hitherto underappreciated non-genetic evolution patterns in ccRCC.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945085","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":"Spatially Resolved Tumor Ecosystems and Cell States in Gastric Adenocarcinoma Progression and Evolution","authors":"Haoran Ma, Supriya Srivastava, Shamaine Wei Ting Ho, Chang Xu, Benedict Shi Xiang Lian, Xuewen Ong, Su Ting Tay, Taotao Sheng, Huey Yew Jeffrey Lum, Siti Aishah Binte Abdul Ghani, Yunqiang Chu, Kie Kyon Huang, Yeek Teck Goh, Minghui Lee, Takeshi Hagihara, Clara Shi Ya Ng, Angie Lay Keng Tan, Yanrong Zhang, Zichen Ding, Feng Zhu, Michelle Shu Wen Ng, Craig Ryan Cecil Joseph, Hui Chen, Zhen Li, Joseph J. Zhao, Sun Young Rha, Ming Teh, Joe Yeong, Wei Peng Yong, Jimmy Bok-Yan So, Raghav Sundar, Patrick Tan","doi":"10.1158/2159-8290.cd-24-0605","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0605","url":null,"abstract":"Gastric cancer (GC) is a major cause of global cancer mortality with high levels of heterogeneity. To explore geospatial interactions in tumor ecosystems, we integrated 2,138 spatial transcriptomic regions-of-interest (ROIs) with 152,423 single-cell expression profiles across 226 GC samples from 121 patients. We observed pervasive expression-based intratumor heterogeneity, recapitulating tumor progression through spatially localized and functionally ordered subgroups associated with specific immune microenvironments, checkpoint profiles, and genetic drivers such as SOX9. Evolutionary phylogenetic analysis revealed two different evolutionary trajectories (branched evolution and internal diaspora evolution) associated with distinct molecular subtypes, clinical prognoses, and stromal neighborhoods including VWF+ ACKR1+ endothelial cells. Spatial analysis of tumor-stromal interfaces across multiple GCs highlighted new ecosystem states not attributable to mere tumor/stroma admixture, landmarked by increased GREM1 expression. Our results provide insights into how the cellular ecosystems of individual GCs are sculpted by tumor intrinsic and extrinsic selective pressures, culminating in individualized patient-specific cancer cartographies.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"30 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936174","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}