Nature cancer最新文献

{"title":"Mapping the functional network of human cancer through machine learning and pan-cancer proteogenomics","authors":"Zhiao Shi, Jonathan T. Lei, John M. Elizarraras, Bing Zhang","doi":"10.1038/s43018-024-00869-z","DOIUrl":"10.1038/s43018-024-00869-z","url":null,"abstract":"Large-scale omics profiling has uncovered a vast array of somatic mutations and cancer-associated proteins, posing substantial challenges for their functional interpretation. Here we present a network-based approach centered on FunMap, a pan-cancer functional network constructed using supervised machine learning on extensive proteomics and RNA sequencing data from 1,194 individuals spanning 11 cancer types. Comprising 10,525 protein-coding genes, FunMap connects functionally associated genes with unprecedented precision, surpassing traditional protein–protein interaction maps. Network analysis identifies functional protein modules, reveals a hierarchical structure linked to cancer hallmarks and clinical phenotypes, provides deeper insights into established cancer drivers and predicts functions for understudied cancer-associated proteins. Additionally, applying graph-neural-network-based deep learning to FunMap uncovers drivers with low mutation frequency. This study establishes FunMap as a powerful and unbiased tool for interpreting somatic mutations and understudied proteins, with broad implications for advancing cancer biology and informing therapeutic strategies. Zhang and colleagues present FunMap, a computational framework that uses a pan-cancer functional map of over 10,000 protein-coding genes to identify functionally associated genes in large-scale datasets.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 1","pages":"205-222"},"PeriodicalIF":23.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813826","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":"Anti-metastatic extracellular vesicles carrying DNA","authors":"Janusz Rak","doi":"10.1038/s43018-024-00829-7","DOIUrl":"10.1038/s43018-024-00829-7","url":null,"abstract":"Cancer cells often secrete extracellular vesicles (EVs), bubble-like structures thought to elicit pro-metastatic states. New work shows that colorectal cancers systemically export their genetic material attached to the surface of specific EVs. These DNA-carrying EVs are taken up by macrophages in the liver, activating anti-metastatic immune responses.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 12","pages":"1793-1795"},"PeriodicalIF":23.5,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770548","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":"Unique structural configuration of EV-DNA primes Kupffer cell-mediated antitumor immunity to prevent metastatic progression","authors":"Inbal Wortzel, Yura Seo, Ife Akano, Lee Shaashua, Gabriel Cardial Tobias, Jakob Hebert, Kyung-A Kim, DooA Kim, Shani Dror, Yanshen Liu, Griffin Campbell Azrak, Michele Cioffi, Kofi Ennu Johnson, Tammy Hennika, Meshulam Zisha Twerski, Alexis Kushner, Robert Math, Yoon Dae Han, Dai Hoon Han, Minsun Jung, Juyeong Park, Soonmyung Paik, Jeon-Soo Shin, Min Goo Lee, Marco Vincenzo Russo, Daniel Zakheim, Jesse Barnes, Sunjoy Mehta, Katia Manova, Robert E. Schwartz, Basant Kumar Thakur, Nancy Boudreau, Irina Matei, Haiying Zhang, Simone Sidoli, Jacqueline Bromberg, Yael David, Han Sang Kim, David Lyden","doi":"10.1038/s43018-024-00862-6","DOIUrl":"10.1038/s43018-024-00862-6","url":null,"abstract":"Extracellular vesicles (EVs) transport biomolecules that mediate intercellular communication. We previously showed that EVs contain DNA (EV-DNA) representing the entire genome. However, the mechanism of genomic EV-DNA packaging and its role in cancer remain elusive. We now demonstrate that EV-DNA is predominantly localized on the vesicle surface and associated with uniquely modified and cleaved histones. Moreover, a genome-wide clustered regularly interspaced short palindromic repeats knockout screen revealed that immune developmental pathways and genes, including apoptotic peptidase activating factor 1 (APAF1) and neutrophil cytosolic factor 1 (NCF1), regulate EV-DNA packaging. Furthermore, in colorectal cancer models, uptake of EV-DNA by pre-metastatic liver Kupffer cells (KCs) activated DNA damage responses. This activation rewired KC cytokine production and promoted the formation of tertiary lymphoid structures, thereby suppressing liver metastasis. Conversely, loss of APAF1 decreased EV-DNA packaging and promoted liver metastasis. Importantly, colorectal cancer biopsy EV-DNA secretion could serve as a predictive biomarker for postoperative metastasis. Taken together, our findings indicate that uniquely chromatinized EV-DNA induces antitumor immunity. Lyden and colleagues find that immune developmental genes, such as apoptotic peptidase activating factor 1 (APAF1), support DNA packaging on the surface of tumor-derived extracellular vesicles that are taken up by resident liver macrophages, thereby suppressing metastasis.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 12","pages":"1815-1833"},"PeriodicalIF":23.5,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770594","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 multiomic atlas identifies a treatment-resistant, bone marrow progenitor-like cell population in T cell acute lymphoblastic leukemia","authors":"Jason Xu, Changya Chen, Jonathan H. Sussman, Satoshi Yoshimura, Tiffaney Vincent, Petri Pölönen, Jianzhong Hu, Shovik Bandyopadhyay, Omar Elghawy, Wenbao Yu, Joseph Tumulty, Chia-hui Chen, Elizabeth Y. Li, Caroline Diorio, Rawan Shraim, Haley Newman, Lahari Uppuluri, Alexander Li, Gregory M. Chen, David W. Wu, Yang-yang Ding, Jessica A. Xu, Damjan Karanfilovski, Tristan Lim, Miles Hsu, Anusha Thadi, Kyung Jin Ahn, Chi-Yun Wu, Jacqueline Peng, Yusha Sun, Alice Wang, Rushabh Mehta, David Frank, Lauren Meyer, Mignon L. Loh, Elizabeth A. Raetz, Zhiguo Chen, Brent L. Wood, Meenakshi Devidas, Kimberly P. Dunsmore, Stuart S. Winter, Ti-Cheng Chang, Gang Wu, Stanley B. Pounds, Nancy R. Zhang, William Carroll, Stephen P. Hunger, Kathrin Bernt, Jun J. Yang, Charles G. Mullighan, Kai Tan, David T. Teachey","doi":"10.1038/s43018-024-00863-5","DOIUrl":"10.1038/s43018-024-00863-5","url":null,"abstract":"Refractoriness to initial chemotherapy and relapse after remission are the main obstacles to curing T cell acute lymphoblastic leukemia (T-ALL). While tumor heterogeneity has been implicated in treatment failure, the cellular and genetic factors contributing to resistance and relapse remain unknown. Here we linked tumor subpopulations with clinical outcome, created an atlas of healthy pediatric hematopoiesis and applied single-cell multiomic analysis to a diverse cohort of 40 T-ALL cases. We identified a bone marrow progenitor (BMP)-like leukemia subpopulation associated with treatment failure and poor overall survival. The single-cell-derived molecular signature of BMP-like blasts predicted poor outcome across multiple subtypes of T-ALL and revealed that NOTCH1 mutations additively drive T-ALL blasts away from the BMP-like state. Through in silico and in vitro drug screenings, we identified a therapeutic vulnerability of BMP-like blasts to apoptosis-inducing agents including venetoclax. Collectively, our study establishes multiomic signatures for rapid risk stratification and targeted treatment of high-risk T-ALL. Tan and colleagues conducted a single-cell multiomic analysis of T cell acute lymphoblastic leukemia and identified a treatment-resistant subpopulation of bone marrow progenitor-like blasts associated with poor outcomes.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 1","pages":"102-122"},"PeriodicalIF":23.5,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11779640/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716449","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":"Bone marrow progenitor-like cells against leukemia cure","authors":"Sarah Elitzur, Shai Izraeli","doi":"10.1038/s43018-024-00864-4","DOIUrl":"10.1038/s43018-024-00864-4","url":null,"abstract":"Relapse in T cell acute lymphoblastic leukemia (T-ALL) constitutes a challenge. A subclonal population of bone marrow progenitor-like cells present in all T-ALL genetic or immunophenotypic subtypes is now shown to confer chemoresistance and poor prognosis, and to be targetable with anti-apoptotic agents.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 1","pages":"18-19"},"PeriodicalIF":23.5,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716450","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":"Evolving cell states and oncogenic drivers during the progression of IDH-mutant gliomas","authors":"Jingyi Wu, L. Nicolas Gonzalez Castro, Sofia Battaglia, Chadi A. El Farran, Joshua P. D’Antonio, Tyler E. Miller, Mario L. Suvà, Bradley E. Bernstein","doi":"10.1038/s43018-024-00865-3","DOIUrl":"10.1038/s43018-024-00865-3","url":null,"abstract":"Isocitrate dehydrogenase (IDH) mutants define a class of gliomas that are initially slow-growing but inevitably progress to fatal disease. To characterize their malignant cell hierarchy, we profiled chromatin accessibility and gene expression across single cells from low-grade and high-grade IDH-mutant gliomas and ascertained their developmental states through a comparison to normal brain cells. We provide evidence that these tumors are initially fueled by slow-cycling oligodendrocyte progenitor cell-like cells. During progression, a more proliferative neural progenitor cell-like population expands, potentially through partial reprogramming of ‘permissive’ chromatin in progenitors. This transition is accompanied by a switch from methylation-based drivers to genetic ones. In low-grade IDH-mutant tumors or organoids, DNA hypermethylation appears to suppress interferon (IFN) signaling, which is induced by IDH or DNA methyltransferase 1 inhibitors. High-grade tumors frequently lose this hypermethylation and instead acquire genetic alterations that disrupt IFN and other tumor-suppressive programs. Our findings explain how these slow-growing tumors may progress to lethal malignancies and have implications for therapies that target their epigenetic underpinnings. Wu et al. perform single-cell analyses to explore the switch from low-grade to high-grade isocitrate-dehydrogenase-mutant glioma and show that it is characterized by oligodendrocyte progenitor cell-like cells transitioning to proliferative neural progenitor cell-like cells.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 1","pages":"145-157"},"PeriodicalIF":23.5,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687340","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":"Transcription and DNA replication collisions lead to large tandem duplications and expose targetable therapeutic vulnerabilities in cancer","authors":"Yang Yang, Michelle L. Badura, Patrick C. O’Leary, Henry M. Delavan, Troy M. Robinson, Emily A. Egusa, Xiaoming Zhong, Jason T. Swinderman, Haolong Li, Meng Zhang, Minkyu Kim, Alan Ashworth, Felix Y. Feng, Jonathan Chou, Lixing Yang","doi":"10.1038/s43018-024-00848-4","DOIUrl":"10.1038/s43018-024-00848-4","url":null,"abstract":"Despite the abundance of somatic structural variations (SVs) in cancer, the underlying molecular mechanisms of their formation remain unclear. In the present study, we used 6,193 whole-genome sequenced tumors to study the contributions of transcription and DNA replication collisions to genome instability. After deconvoluting robust SV signatures in three independent pan-cancer cohorts, we detected transcription-dependent, replicated-strand bias, the expected footprint of transcription–replication collision (TRC), in large tandem duplications (TDs). Large TDs are abundant in female-enriched, upper gastrointestinal tract and prostate cancers. They are associated with poor patient survival and mutations in TP53, CDK12 and SPOP. Upon inactivating CDK12, cells display significantly more TRCs, R-loops and large TDs. Inhibition of WEE1, CHK1 and ATR selectively inhibits the growth of cells deficient in CDK12. Our data suggest that large TDs in cancer form as a result of TRCs and their presence can be used as a biomarker for prognosis and treatment. Yang et al. show that transcription–replication collisions lead to large tandem duplications, which are frequent in female-enriched, upper gastrointestinal tract and prostate cancers and are associated with poor survival and mutations in specific genes, such as CDK12.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 12","pages":"1885-1901"},"PeriodicalIF":23.5,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668246","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":"Single-cell transcriptomic landscape deciphers olfactory neuroblastoma subtypes and intra-tumoral heterogeneity","authors":"Jingyi Yang, Xiaole Song, Huankang Zhang, Quan Liu, Ruoyan Wei, Luo Guo, Cuncun Yuan, Fu Chen, Kai Xue, Yuting Lai, Li Wang, Junfeng Shi, Chengle Zhou, Juan Wang, Yingxuan Yu, Qibing Mei, Li Hu, Huan Wang, Chen Zhang, Qianqian Zhang, Houyong Li, Ye Gu, Weidong Zhao, Huapeng Yu, Jingjing Wang, Zhuofu Liu, Han Li, Shixing Zheng, Juan Liu, Lu Yang, Wanpeng Li, Rui Xu, Jiani Chen, Yumin Zhou, Xiankui Cheng, Yiqun Yu, Dehui Wang, Xicai Sun, Hongmeng Yu","doi":"10.1038/s43018-024-00855-5","DOIUrl":"10.1038/s43018-024-00855-5","url":null,"abstract":"Olfactory neuroblastoma (ONB) is a rare malignancy known to originate from the olfactory epithelium. The complex tumor ecosystem of this pathology remains unclear. Here, we explored the cellular components within ten ONB tumors and one olfactory mucosa sample based on single-cell RNA profiles. We showed the intra-tumoral heterogeneity by identifying five unique expression programs among malignant epithelial cells. A distinct three-classification system (neural, basal, mesenchymal) for ONB was established according to the distinguished gene expression patterns. Biomarkers for categorizing bulk tumors into uncharacterized subtypes were elucidated. Different responses towards certain chemotherapy regimens could be cautiously inferred according to the molecular features representing the three tumor types, thus helping with precision chemotherapy. We also analyzed subclusters of the tumor microenvironment (TME) and the interactions among different cell types within the TME. The relative abundance of immunosuppressive tumor-associated macrophages suggests potential benefits of immunotherapies targeting macrophages. Yu and colleagues present a single-cell transcriptomic landscape of olfactory neuroblastoma, characterizing different tumor subtypes and cancer cell responses to drug treatments.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 12","pages":"1919-1939"},"PeriodicalIF":23.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623725","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":"The pro-oncogenic noncanonical activity of a RAS•GTP:RanGAP1 complex facilitates nuclear protein export","authors":"Brajendra K. Tripathi, Nicole H. Hirsh, Xiaolan Qian, Marian E. Durkin, Dunrui Wang, Alex G. Papageorge, Ross Lake, Yvonne A. Evrard, Adam I. Marcus, Suresh S. Ramalingam, Mary Dasso, Karen H. Vousden, James H. Doroshow, Kylie J. Walters, Douglas R. Lowy","doi":"10.1038/s43018-024-00847-5","DOIUrl":"10.1038/s43018-024-00847-5","url":null,"abstract":"Canonical RAS signaling, including PI3K/AKT- and RAF/MEK-dependent activities, results mainly from RAS•GTP interaction with its effectors at the plasma membrane. Here, we identified a fundamental, oncogenic, noncanonical RAS•GTP activity that increases XPO1-dependent export of nuclear protein cargo into the cytoplasm and is independent of PI3K/AKT and RAF/MEK signaling. This RAS-dependent step acts downstream from XPO1 binding to nuclear protein cargo and is mediated by a perinuclear protein complex between RAS•GTP and RanGAP1 that facilitates hydrolysis of Ran•GTP to Ran•GDP, which promotes release of nuclear protein cargo into the cytoplasm. The export of nuclear EZH2, which promotes cytoplasmic degradation of the DLC1 tumor suppressor protein, is a biologically important component of this pro-oncogenic activity. Conversely, preventing nuclear protein export contributes to the antitumor activity of KRAS inhibition, which can be further augmented by reactivating the tumor suppressor activity of DLC1 or potentially combining RAS inhibitors with other cancer treatments. Tripathi et al. identify a noncanonical RAS•GTP activity that increases XPO1-dependent export of nuclear proteins into the cytoplasm. This depends on a RAS–RanGAP1 complex, and this export function contributes to RAS oncogenic activity.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 12","pages":"1902-1918"},"PeriodicalIF":23.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43018-024-00847-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623737","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":"Modeling adenoma–carcinoma progression from a single MLH1-knockout cell via colon organoids","authors":"","doi":"10.1038/s43018-024-00842-w","DOIUrl":"10.1038/s43018-024-00842-w","url":null,"abstract":"Starting from a single MLH1-knockout human colon cell, we modeled the transition of daughter cells and resultant organoids from normal epithelium to carcinoma by sequentially selecting cells with spontaneously acquired mutations. The mutations were those common in patients who have Lynch syndrome-associated colorectal cancer with high microsatellite instability, and induced insensitivity to growth factors that restrict the growth of adult stem cells.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 12","pages":"1798-1799"},"PeriodicalIF":23.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623521","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}