Nature cancer最新文献

{"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":"<p><p>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.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"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":"https://doi.org/10.1038/s43018-024-00855-5","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"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":"https://doi.org/10.1038/s43018-024-00847-5","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/10.1038/s43018-024-00842-w","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"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}

{"title":"Recapitulating the adenoma-carcinoma sequence by selection of four spontaneous oncogenic mutations in mismatch-repair-deficient human colon organoids.","authors":"Tomohiro Mizutani, Matteo Boretto, Sangho Lim, Jarno Drost, Diego Montiel González, Rurika Oka, Maarten H Geurts, Harry Begthel, Jeroen Korving, Johan H van Es, Ruben van Boxtel, Hans Clevers","doi":"10.1038/s43018-024-00841-x","DOIUrl":"10.1038/s43018-024-00841-x","url":null,"abstract":"<p><p>Carcinogenesis results from the sequential acquisition of oncogenic mutations that convert normal cells into invasive, metastasizing cancer cells. Colorectal cancer exemplifies this process through its well-described adenoma-carcinoma sequence, modeled previously using clustered regularly interspaced short palindromic repeats (CRISPR) to induce four consecutive mutations in wild-type human gut organoids. Here, we demonstrate that long-term culture of mismatch-repair-deficient organoids allows the selection of spontaneous oncogenic mutations through the sequential withdrawal of Wnt agonists, epidermal growth factor (EGF) agonists and the bone morphogenetic protein (BMP) antagonist Noggin, while TP53 mutations were selected through the addition of Nutlin-3. Thus, organoids sequentially acquired mutations in AXIN1 and AXIN2 (Wnt pathway), TP53, ACVR2A and BMPR2 (BMP pathway) and NRAS (EGF pathway), gaining complete independence from stem cell niche factors. Quadruple-pathway (Wnt, EGF receptor, p53 and BMP) mutant organoids formed solid tumors upon xenotransplantation. This demonstrates that carcinogenesis can be recapitulated in a DNA repair-mutant background through in vitro selection that targets four consecutive cancer pathways.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564728","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":"Defining the transcriptional lineages of breast cancer subtypes.","authors":"","doi":"10.1038/s43018-024-00774-5","DOIUrl":"https://doi.org/10.1038/s43018-024-00774-5","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546460","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":"Global loss of promoter-enhancer connectivity and rebalancing of gene expression during early colorectal cancer carcinogenesis.","authors":"Yizhou Zhu, Hayan Lee, Shannon White, Annika K Weimer, Emma Monte, Aaron Horning, Stephanie A Nevins, Edward D Esplin, Kristina Paul, Gat Krieger, Zohar Shipony, Roxanne Chiu, Rozelle Laquindanum, Thomas V Karathanos, Melissa W Y Chua, Meredith Mills, Uri Ladabaum, Teri Longacre, Jeanne Shen, Ariel Jaimovich, Doron Lipson, Anshul Kundaje, William J Greenleaf, Christina Curtis, James M Ford, Michael P Snyder","doi":"10.1038/s43018-024-00823-z","DOIUrl":"https://doi.org/10.1038/s43018-024-00823-z","url":null,"abstract":"<p><p>Although three-dimensional (3D) genome architecture is crucial for gene regulation, its role in disease remains elusive. We traced the evolution and malignant transformation of colorectal cancer (CRC) by generating high-resolution chromatin conformation maps of 33 colon samples spanning different stages of early neoplastic growth in persons with familial adenomatous polyposis (FAP). Our analysis revealed a substantial progressive loss of genome-wide cis-regulatory connectivity at early malignancy stages, correlating with nonlinear gene regulation effects. Genes with high promoter-enhancer (P-E) connectivity in unaffected mucosa were not linked to elevated baseline expression but tended to be upregulated in advanced stages. Inhibiting highly connected promoters preferentially represses gene expression in CRC cells compared to normal colonic epithelial cells. Our results suggest a two-phase model whereby neoplastic transformation reduces P-E connectivity from a redundant state to a rate-limiting one for transcriptional levels, highlighting the intricate interplay between 3D genome architecture and gene regulation during early CRC progression.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546462","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":"Differential chromatin accessibility and transcriptional dynamics define breast cancer subtypes and their lineages.","authors":"Michael D Iglesia, Reyka G Jayasinghe, Siqi Chen, Nadezhda V Terekhanova, John M Herndon, Erik Storrs, Alla Karpova, Daniel Cui Zhou, Nataly Naser Al Deen, Andrew T Shinkle, Rita Jui-Hsien Lu, Wagma Caravan, Andrew Houston, Yanyan Zhao, Kazuhito Sato, Preet Lal, Cherease Street, Fernanda Martins Rodrigues, Austin N Southard-Smith, André Luiz N Targino da Costa, Houxiang Zhu, Chia-Kuei Mo, Lisa Crowson, Robert S Fulton, Matthew A Wyczalkowski, Catrina C Fronick, Lucinda A Fulton, Hua Sun, Sherri R Davies, Elizabeth L Appelbaum, Sara E Chasnoff, Madelyn Carmody, Candace Brooks, Ruiyang Liu, Michael C Wendl, Clara Oh, Diane Bender, Carlos Cruchaga, Oscar Harari, Andrea Bredemeyer, Kory Lavine, Ron Bose, Julie Margenthaler, Jason M Held, Samuel Achilefu, Foluso Ademuyiwa, Rebecca Aft, Cynthia Ma, Graham A Colditz, Tao Ju, Stephen T Oh, James Fitzpatrick, E Shelley Hwang, Kooresh I Shoghi, Milan G Chheda, Deborah J Veis, Feng Chen, Ryan C Fields, William E Gillanders, Li Ding","doi":"10.1038/s43018-024-00773-6","DOIUrl":"10.1038/s43018-024-00773-6","url":null,"abstract":"<p><p>Breast cancer (BC) is defined by distinct molecular subtypes with different cells of origin. The transcriptional networks that characterize the subtype-specific tumor-normal lineages are not established. In this work, we applied bulk, single-cell and single-nucleus multi-omic techniques as well as spatial transcriptomics and multiplex imaging on 61 samples from 37 patients with BC to show characteristic links in gene expression and chromatin accessibility between BC subtypes and their putative cells of origin. Regulatory network analysis of transcription factors underscored the importance of BHLHE40 in luminal BC and luminal mature cells and KLF5 in basal-like tumors and luminal progenitor cells. Furthermore, we identify key genes defining the basal-like (SOX6 and KCNQ3) and luminal A/B (FAM155A and LRP1B) lineages. Exhausted CTLA4-expressing CD8⁺ T cells were enriched in basal-like BC, suggesting an altered means of immune dysfunction. These findings demonstrate analysis of paired transcription and chromatin accessibility at the single-cell level is a powerful tool for investigating cancer lineage and highlight transcriptional networks that define basal and luminal BC lineages.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546461","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 3D genome view of colon cancer initiation.","authors":"Adi Danieli-Mackay, Argyris Papantonis","doi":"10.1038/s43018-024-00825-x","DOIUrl":"https://doi.org/10.1038/s43018-024-00825-x","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546459","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":"Multiomic analysis of familial adenomatous polyposis reveals molecular pathways associated with early tumorigenesis.","authors":"Edward D Esplin, Casey Hanson, Si Wu, Aaron M Horning, Nasim Barapour, Stephanie A Nevins, Lihua Jiang, Kévin Contrepois, Hayan Lee, Tuhin K Guha, Zheng Hu, Rozelle Laquindanum, Meredith A Mills, Hassan Chaib, Roxanne Chiu, Ruiqi Jian, Joanne Chan, Mathew Ellenberger, Winston R Becker, Bahareh Bahmani, Aziz Khan, Basil Michael, Annika K Weimer, D Glen Esplin, Jeanne Shen, Samuel Lancaster, Emma Monte, Thomas V Karathanos, Uri Ladabaum, Teri A Longacre, Anshul Kundaje, Christina Curtis, William J Greenleaf, James M Ford, Michael P Snyder","doi":"10.1038/s43018-024-00831-z","DOIUrl":"https://doi.org/10.1038/s43018-024-00831-z","url":null,"abstract":"<p><p>Familial adenomatous polyposis (FAP) is a genetic disease causing hundreds of premalignant polyps in affected persons and is an ideal model to study transitions of early precancer states to colorectal cancer (CRC). We performed deep multiomic profiling of 93 samples, including normal mucosa, benign polyps and dysplastic polyps, from six persons with FAP. Transcriptomic, proteomic, metabolomic and lipidomic analyses revealed a dynamic choreography of thousands of molecular and cellular events that occur during precancerous transitions toward cancer formation. These involve processes such as cell proliferation, immune response, metabolic alterations (including amino acids and lipids), hormones and extracellular matrix proteins. Interestingly, activation of the arachidonic acid pathway was found to occur early in hyperplasia; this pathway is targeted by aspirin and other nonsteroidal anti-inflammatory drugs, a preventative treatment under investigation in persons with FAP. Overall, our results reveal key genomic, cellular and molecular events during the earliest steps in CRC formation and potential mechanisms of pharmaceutical prophylaxis.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546463","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}