Nature cancer最新文献

{"title":"The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1.","authors":"Rodrigo Romero, Tinyi Chu, Tania J González Robles, Perianne Smith, Yubin Xie, Harmanpreet Kaur, Sara Yoder, Huiyong Zhao, Chenyi Mao, Wenfei Kang, Maria V Pulina, Kayla E Lawrence, Anuradha Gopalan, Samir Zaidi, Kwangmin Yoo, Jungmin Choi, Ning Fan, Olivia Gerstner, Wouter R Karthaus, Elisa DeStanchina, Kelly V Ruggles, Peter M K Westcott, Ronan Chaligné, Dana Pe'er, Charles L Sawyers","doi":"10.1038/s43018-024-00838-6","DOIUrl":"10.1038/s43018-024-00838-6","url":null,"abstract":"<p><p>Lineage plasticity is a hallmark of cancer progression that impacts therapy outcomes, yet the mechanisms mediating this process remain unclear. Here, we introduce a versatile in vivo platform to interrogate neuroendocrine lineage transformation throughout prostate cancer progression. Transplanted mouse prostate organoids with human-relevant driver mutations (Rb1^-/-; Trp53^-/-; cMyc⁺ or Pten^-/-; Trp53^-/-; cMyc⁺) develop adenocarcinomas, but only those with Rb1 deletion advance to aggressive, ASCL1⁺ neuroendocrine prostate cancer (NEPC) resistant to androgen receptor signaling inhibitors. Notably, this transition requires an in vivo microenvironment not replicated by conventional organoid culture. Using multiplexed immunofluorescence and spatial transcriptomics, we reveal that ASCL1⁺ cells arise from KRT8⁺ luminal cells, progressing into transcriptionally heterogeneous ASCL1⁺;KRT8^- NEPC. Ascl1 loss in established NEPC causes transient regression followed by recurrence, but its deletion before transplantation abrogates lineage plasticity, resulting in castration-sensitive adenocarcinomas. This dynamic model highlights the importance of therapy timing and offers a platform to identify additional lineage plasticity drivers.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406623","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":"Publisher Correction: Integrative proteogenomic profiling of high-risk prostate cancer samples from Chinese patients indicates metabolic vulnerabilities and diagnostic biomarkers.","authors":"Baijun Dong, Jun-Yu Xu, Yuqi Huang, Jiacheng Guo, Qun Dong, Yanqing Wang, Ni Li, Qiuli Liu, Mingya Zhang, Qiang Pan, Hanling Wang, Jun Jiang, Bairun Chen, Danqing Shen, Yiming Ma, Linhui Zhai, Jian Zhang, Jing Li, Wei Xue, Minjia Tan, Jun Qin","doi":"10.1038/s43018-024-00845-7","DOIUrl":"https://doi.org/10.1038/s43018-024-00845-7","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365854","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":"CAR-redirected natural killer T cells demonstrate superior antitumor activity to CAR-T cells through multimodal CD1d-dependent mechanisms.","authors":"Xin Zhou, Ying Wang, Zhangqi Dou, Gloria Delfanti, Ourania Tsahouridis, Caroline Marnata Pellegry, Manuela Zingarelli, Gatphan Atassi, Mark G Woodcock, Giulia Casorati, Paolo Dellabona, William Y Kim, Linjie Guo, Barbara Savoldo, Ageliki Tsagaratou, J Justin Milner, Leonid S Metelitsa, Gianpietro Dotti","doi":"10.1038/s43018-024-00830-0","DOIUrl":"10.1038/s43018-024-00830-0","url":null,"abstract":"<p><p>Human natural killer T (NKT) cells have been proposed as a promising cell platform for chimeric antigen receptor (CAR) therapy in solid tumors. Here we generated murine CAR-NKT cells and compared them with CAR-T cells in immune-competent mice. Both CAR-NKT cells and CAR-T cells showed similar antitumor effects in vitro, but CAR-NKT cells showed superior antitumor activity in vivo via CD1d-dependent immune responses in the tumor microenvironment. Specifically, we show that CAR-NKT cells eliminate CD1d-expressing M2-like macrophages. In addition, CAR-NKT cells promote epitope spreading and activation of endogenous T cell responses against tumor-associated neoantigens. Finally, we observed that CAR-NKT cells can co-express PD1 and TIM3 and show an exhaustion phenotype in a model of high tumor burden. PD1 blockade as well as vaccination augmented the antitumor activity of CAR-NKT cells. In summary, our results demonstrate the multimodal function of CAR-NKT cells in solid tumors, further supporting the rationale for developing CAR-NKT therapies in the clinic.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142361808","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":"Co-targeting metabolism and epigenetics in MDS with telaglenastat and azacytidine","authors":"","doi":"10.1038/s43018-024-00812-2","DOIUrl":"10.1038/s43018-024-00812-2","url":null,"abstract":"Azacytidine is used as standard treatment for myelodysplastic syndrome (MDS) but, although it induces responses, remissions are rare and not durable. In patients with MDS, malignant cells rely on glutamine for survival and exhibit elevated levels of glutaminase, an essential enzyme for glutamine metabolism. Our results from preclinical and clinical studies demonstrate the effectiveness of combining the glutaminase inhibitor telaglenastat with azacytidine in advanced MDS.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350423","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":"Spatial single-cell protein landscape reveals vimentinhigh macrophages as immune-suppressive in the microenvironment of hepatocellular carcinoma","authors":"Xinyao Qiu,&nbsp;Tao Zhou,&nbsp;Shuai Li,&nbsp;Jianmin Wu,&nbsp;Jing Tang,&nbsp;Guosheng Ma,&nbsp;Shuai Yang,&nbsp;Ji Hu,&nbsp;Kaiting Wang,&nbsp;Siyun Shen,&nbsp;Hongyang Wang,&nbsp;Lei Chen","doi":"10.1038/s43018-024-00824-y","DOIUrl":"10.1038/s43018-024-00824-y","url":null,"abstract":"Tumor microenvironment heterogeneity in hepatocellular carcinoma (HCC) on a spatial single-cell resolution is unclear. Here, we conducted co-detection by indexing to profile the spatial heterogeneity of 401 HCC samples with 36 biomarkers. By parsing the spatial tumor ecosystem of liver cancer, we identified spatial patterns with distinct prognosis and genomic and molecular features, and unveiled the progressive role of vimentin (VIM)high macrophages. Integration analysis with eight independent cohorts demonstrated that the spatial co-occurrence of VIMhigh macrophages and regulatory T cells promotes tumor progression and favors immunotherapy. Functional studies further demonstrated that VIMhigh macrophages enhance the immune-suppressive activity of regulatory T cells by mechanistically increasing the secretion of interleukin-1β. Our data provide deep insights into the heterogeneity of tumor microenvironment architecture and unveil the critical role of VIMhigh macrophages during HCC progression, which holds potential for personalized cancer prevention and drug discovery and reinforces the need to resolve spatial-informed features for cancer treatment. Qui et al. perform co-detection by indexing profiling of 401 hepatocellular carcinoma patient samples and identify a role for vimentinhigh macrophages in instructing an immune-suppressive microenvironment by enhancing the suppressive activity of regulatory T cells via interleukin-1β.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350424","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":"Spatial analysis reveals targetable macrophage-mediated mechanisms of immune evasion in hepatocellular carcinoma minimal residual disease","authors":"Lea Lemaitre,&nbsp;Nia Adeniji,&nbsp;Akanksha Suresh,&nbsp;Reshma Reguram,&nbsp;Josephine Zhang,&nbsp;Jangho Park,&nbsp;Amit Reddy,&nbsp;Alexandro E. Trevino,&nbsp;Aaron T. Mayer,&nbsp;Anja Deutzmann,&nbsp;Aida S. Hansen,&nbsp;Ling Tong,&nbsp;Vinodhini Arjunan,&nbsp;Neeraja Kambham,&nbsp;Brendan C. Visser,&nbsp;Monica M. Dua,&nbsp;C. Andrew Bonham,&nbsp;Nishita Kothary,&nbsp;H. Blaize D’Angio,&nbsp;Ryan Preska,&nbsp;Yanay Rosen,&nbsp;James Zou,&nbsp;Vivek Charu,&nbsp;Dean W. Felsher,&nbsp;Renumathy Dhanasekaran","doi":"10.1038/s43018-024-00828-8","DOIUrl":"10.1038/s43018-024-00828-8","url":null,"abstract":"Hepatocellular carcinoma (HCC) frequently recurs from minimal residual disease (MRD), which persists after therapy. Here, we identified mechanisms of persistence of residual tumor cells using post-chemoembolization human HCC (n = 108 patients, 1.07 million cells) and a transgenic mouse model of MRD. Through single-cell high-plex cytometric imaging, we identified a spatial neighborhood within which PD-L1 + M2-like macrophages interact with stem-like tumor cells, correlating with CD8+ T cell exhaustion and poor survival. Further, through spatial transcriptomics of residual HCC, we showed that macrophage-derived TGFβ1 mediates the persistence of stem-like tumor cells. Last, we demonstrate that combined blockade of Pdl1 and Tgfβ excluded immunosuppressive macrophages, recruited activated CD8+ T cells and eliminated residual stem-like tumor cells in two mouse models: a transgenic model of MRD and a syngeneic orthotopic model of doxorubicin-resistant HCC. Thus, our spatial analyses reveal that PD-L1+ macrophages sustain MRD by activating the TGFβ pathway in stem-like cancer cells and targeting this interaction may prevent HCC recurrence from MRD. Dhanasekaran and colleagues study minimal residual disease in hepatocellular carcinoma using single-cell spatial transcriptomic and proteomic analysis and find a targetable role for immunosuppressive macrophages.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291578","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":"Leveraging the potential for deintensification in cancer care.","authors":"Jennifer A Soon, Fanny Franchini, Maarten J IJzerman, Grant A McArthur","doi":"10.1038/s43018-024-00827-9","DOIUrl":"https://doi.org/10.1038/s43018-024-00827-9","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291572","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":"Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: a phase 1b/2 clinical trial and correlative analyses","authors":"Courtney D. DiNardo,&nbsp;Divij Verma,&nbsp;Natalia Baran,&nbsp;Tushar D. Bhagat,&nbsp;Anna Skwarska,&nbsp;Alessia Lodi,&nbsp;Kapil Saxena,&nbsp;Tianyu Cai,&nbsp;Xiaoping Su,&nbsp;Veronica A. Guerra,&nbsp;Gowri Poigaialwar,&nbsp;Vinitha M. Kuruvilla,&nbsp;Sergej Konoplev,&nbsp;Shanisha Gordon-Mitchell,&nbsp;Kith Pradhan,&nbsp;Srinivas Aluri,&nbsp;G. Lavender Hackman,&nbsp;Sovira Chaudhry,&nbsp;Meghan Collins,&nbsp;Shannon R. Sweeney,&nbsp;Jonathan Busquets,&nbsp;Atul Singh Rathore,&nbsp;Qing Deng,&nbsp;Michael R. Green,&nbsp;Steven Grant,&nbsp;Susan Demo,&nbsp;Gaurav S. Choudhary,&nbsp;Srabani Sahu,&nbsp;Beamon Agarwal,&nbsp;Mason Spodek,&nbsp;Victor Thiruthuvanathan,&nbsp;Britta Will,&nbsp;Ulrich Steidl,&nbsp;George D. Tippett,&nbsp;Jan Burger,&nbsp;Gautam Borthakur,&nbsp;Elias Jabbour,&nbsp;Naveen Pemmaraju,&nbsp;Tapan Kadia,&nbsp;Steven Kornblau,&nbsp;Naval G. Daver,&nbsp;Kiran Naqvi,&nbsp;Nicholas J. Short,&nbsp;Guillermo Garcia-Manero,&nbsp;Stefano Tiziani,&nbsp;Amit Verma,&nbsp;Marina Konopleva","doi":"10.1038/s43018-024-00811-3","DOIUrl":"10.1038/s43018-024-00811-3","url":null,"abstract":"Malignancies are reliant on glutamine as an energy source and a facilitator of aberrant DNA methylation. We demonstrate preclinical synergy of telaglenastat (CB-839), a selective glutaminase inhibitor, combined with azacytidine (AZA), followed by a single-arm, open-label, phase 1b/2 study in persons with advanced myelodysplastic syndrome (MDS). The dual primary endpoints evaluated clinical activity, safety and tolerability; secondary endpoints evaluated pharmacokinetics, pharmacodynamics, overall survival, event-free survival and duration of response. The dose-escalation study included six participants and the dose-expansion study included 24 participants. Therapy was well tolerated and led to an objective response rate of 70% with (marrow) complete remission in 53% of participants and a median overall survival of 11.6 months, with evidence of myeloid differentiation in responders determined by single-cell RNA sequencing. Glutamine transporter solute carrier family 38 member 1 in MDS stem cells was associated with clinical responses and predictive of worse prognosis in a large MDS cohort. These data demonstrate the safety and efficacy of CB-839 and AZA as a combined metabolic and epigenetic approach in MDS. ClinicalTrials.gov identifier: NCT03047993 . DiNardo et al. perform a phase 1b/2 clinical trial of telaglenastat (CB-839) in combination with azacytidine in persons with advanced myelodysplastic syndromes and report on the treatment safety and efficacy, including a definition of clinical responders.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253739","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":"Deciphering the response to BCMA CAR T cell therapy","authors":"Hamza Hassan,&nbsp;Marco L. Davila","doi":"10.1038/s43018-024-00826-w","DOIUrl":"10.1038/s43018-024-00826-w","url":null,"abstract":"Despite the promise of chimeric antigen receptor (CAR) T cell therapy, predicting patient response is challenging. Single-cell multiomics of myeloma treated with B cell maturation antigen (BCMA)-targeted CAR T cells now reveal that poor clinical response is associated with an immunosuppressive environment and CAR T cells transition to exhausted phenotypes, indicating a mechanism for reduced persistence.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253738","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":"Vascular heterogeneity of tight junction Claudins guides organotropic metastasis","authors":"Xunian Zhou,&nbsp;Valerie S. LeBleu,&nbsp;Eliot Fletcher-Sananikone,&nbsp;Jiha Kim,&nbsp;Jianli Dai,&nbsp;Bingrui Li,&nbsp;Chia-Chin Wu,&nbsp;Hikaru Sugimoto,&nbsp;Toru Miyake,&nbsp;Lisa M. Becker,&nbsp;Olga V. Volpert,&nbsp;Erica Lawson,&nbsp;Cristina Espinosa Da Silva,&nbsp;Sarah I. Patel,&nbsp;Akane Kizu,&nbsp;Ehsan A. Ehsanipour,&nbsp;Di Sha,&nbsp;Jose Antonio Karam,&nbsp;Kathleen M. McAndrews,&nbsp;Raghu Kalluri","doi":"10.1038/s43018-024-00813-1","DOIUrl":"10.1038/s43018-024-00813-1","url":null,"abstract":"Carcinomas are associated with metastasis to specific organs while sparing others. Breast cancer presents with lung metastasis but rarely kidney metastasis. Using this difference as an example, we queried the mechanism(s) behind the proclivity for organ-specific metastasis. We used spontaneous and implant models of metastatic mammary carcinoma coupled with inflammatory tissue fibrosis, single-cell sequencing analyses and functional studies to unravel the causal determinants of organ-specific metastasis. Here we show that lung metastasis is facilitated by angiopoietin 2 (Ang2)-mediated suppression of lung-specific endothelial tight junction protein Claudin 5, which is augmented by the inflammatory fibrotic microenvironment and prevented by anti-Ang2 blocking antibodies, while kidney metastasis is prevented by non-Ang2-responsive Claudins 2 and 10. Suppression of Claudins 2 and 10 was sufficient to induce the emergence of kidney metastasis. This study illustrates the influence of organ-specific vascular heterogeneity in determining organotropic metastasis, independent of cancer cell-intrinsic mechanisms. Kalluri and colleagues use mammary carcinoma models to study the causes of metastatic organotropism and find an organ-specific role for angiopoietin 2 in driving lung metastasis through the suppression of the tight junction protein Claudin 5.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253741","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}