Nature cancerPub Date : 2024-10-22DOI: 10.1038/s43018-024-00844-8
Leona A Nease, Kellsey P Church, Ines Delclaux, Shino Murakami, Maider Astorkia, Marwa Zerhouni, Graciela Cascio, Riley O Hughes, Kelsey N Aguirre, Paul Zumbo, Lukas E Dow, Samie Jaffrey, Doron Betel, Elena Piskounova
{"title":"Selenocysteine tRNA methylation promotes oxidative stress resistance in melanoma metastasis.","authors":"Leona A Nease, Kellsey P Church, Ines Delclaux, Shino Murakami, Maider Astorkia, Marwa Zerhouni, Graciela Cascio, Riley O Hughes, Kelsey N Aguirre, Paul Zumbo, Lukas E Dow, Samie Jaffrey, Doron Betel, Elena Piskounova","doi":"10.1038/s43018-024-00844-8","DOIUrl":"10.1038/s43018-024-00844-8","url":null,"abstract":"<p><p>Selenocysteine-containing proteins play a central role in redox homeostasis. Their translation is a highly regulated process and is dependent on two tRNA<sup>Sec</sup> isodecoders differing by a single 2'-O-ribose methylation called Um34. Here we characterized FTSJ1 as the Um34 methyltransferase and show that its activity is required for efficient selenocysteine insertion at the UGA stop codon during translation. Specifically, loss of Um34 leads to ribosomal stalling and decreased UGA recoding. FTSJ1-deficient cells are more sensitive to oxidative stress and show decreased metastatic colonization in xenograft models of melanoma metastasis. We found that FTSJ1 mediates efficient translation of selenoproteins essential for the cellular antioxidant response. Our findings uncover a role for tRNA<sup>Sec</sup> Um34 modification in oxidative stress resistance and highlight FTSJ1 as a potential therapeutic target specific for metastatic disease.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504437","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}
Nature cancerPub Date : 2024-10-16DOI: 10.1038/s43018-024-00839-5
Khalil Kass Youssef, Nitin Narwade, Aida Arcas, Angel Marquez-Galera, Raúl Jiménez-Castaño, Cristina Lopez-Blau, Hassan Fazilaty, David García-Gutierrez, Amparo Cano, Joan Galcerán, Gema Moreno-Bueno, Jose P Lopez-Atalaya, M Angela Nieto
{"title":"Two distinct epithelial-to-mesenchymal transition programs control invasion and inflammation in segregated tumor cell populations.","authors":"Khalil Kass Youssef, Nitin Narwade, Aida Arcas, Angel Marquez-Galera, Raúl Jiménez-Castaño, Cristina Lopez-Blau, Hassan Fazilaty, David García-Gutierrez, Amparo Cano, Joan Galcerán, Gema Moreno-Bueno, Jose P Lopez-Atalaya, M Angela Nieto","doi":"10.1038/s43018-024-00839-5","DOIUrl":"https://doi.org/10.1038/s43018-024-00839-5","url":null,"abstract":"<p><p>Epithelial-to-mesenchymal transition (EMT) triggers cell plasticity in embryonic development, adult injured tissues and cancer. Combining the analysis of EMT in cell lines, embryonic neural crest and mouse models of renal fibrosis and breast cancer, we find that there is not a cancer-specific EMT program. Instead, cancer cells dedifferentiate and bifurcate into two distinct and segregated cellular trajectories after activating either embryonic-like or adult-like EMTs to drive dissemination or inflammation, respectively. We show that SNAIL1 acts as a pioneer factor in both EMT trajectories, and PRRX1 drives the progression of the embryonic-like invasive trajectory. We also find that the two trajectories are plastic and interdependent, as the abrogation of the EMT invasive trajectory by deleting Prrx1 not only prevents metastasis but also enhances inflammation, increasing the recruitment of antitumor macrophages. Our data unveil an additional role for EMT in orchestrating intratumor heterogeneity, driving the distribution of functions associated with either inflammation or metastatic dissemination.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470342","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}
Nature cancerPub Date : 2024-10-15DOI: 10.1038/s43018-024-00840-y
Risa Burr, Ignaty Leshchiner, Christina L Costantino, Martin Blohmer, Tilak Sundaresan, Justin Cha, Karsen Seeger, Sara Guay, Brian P Danysh, Ira Gore, Raquel A Jacobs, Kara Slowik, Filippo Utro, Kahn Rhrissorrakrai, Chaya Levovitz, Jaimie L Barth, Taronish Dubash, Brian Chirn, Laxmi Parida, Lecia V Sequist, Jochen K Lennerz, Mari Mino-Kenudson, Shyamala Maheswaran, Kamila Naxerova, Gad Getz, Daniel A Haber
{"title":"Developmental mosaicism underlying EGFR-mutant lung cancer presenting with multiple primary tumors.","authors":"Risa Burr, Ignaty Leshchiner, Christina L Costantino, Martin Blohmer, Tilak Sundaresan, Justin Cha, Karsen Seeger, Sara Guay, Brian P Danysh, Ira Gore, Raquel A Jacobs, Kara Slowik, Filippo Utro, Kahn Rhrissorrakrai, Chaya Levovitz, Jaimie L Barth, Taronish Dubash, Brian Chirn, Laxmi Parida, Lecia V Sequist, Jochen K Lennerz, Mari Mino-Kenudson, Shyamala Maheswaran, Kamila Naxerova, Gad Getz, Daniel A Haber","doi":"10.1038/s43018-024-00840-y","DOIUrl":"10.1038/s43018-024-00840-y","url":null,"abstract":"<p><p>Although the development of multiple primary tumors in smokers with lung cancer can be attributed to carcinogen-induced field cancerization, the occurrence of multiple tumors at presentation in individuals with EGFR-mutant lung cancer who lack known environmental exposures remains unexplained. In the present study, we identified ten patients with early stage, resectable, non-small cell lung cancer who presented with multiple, anatomically distinct, EGFR-mutant tumors. We analyzed the phylogenetic relationships among multiple tumors from each patient using whole-exome sequencing (WES) and hypermutable poly(guanine) (poly(G)) repeat genotyping as orthogonal methods for lineage tracing. In four patients, developmental mosaicism, assessed by WES and poly(G) lineage tracing, indicates a common non-germline cell of origin. In two other patients, we identified germline EGFR variants, which confer moderately enhanced signaling when modeled in vitro. Thus, in addition to germline variants, developmental mosaicism defines a distinct mechanism of genetic predisposition to multiple EGFR-mutant primary tumors, with implications for their etiology and clinical management.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470341","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}
Nature cancerPub Date : 2024-10-11DOI: 10.1038/s43018-024-00838-6
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
{"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<sup>-/-</sup>; Trp53<sup>-/-</sup>; cMyc<sup>+</sup> or Pten<sup>-/-</sup>; Trp53<sup>-/-</sup>; cMyc<sup>+</sup>) develop adenocarcinomas, but only those with Rb1 deletion advance to aggressive, ASCL1<sup>+</sup> 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<sup>+</sup> cells arise from KRT8<sup>+</sup> luminal cells, progressing into transcriptionally heterogeneous ASCL1<sup>+</sup>;KRT8<sup>-</sup> 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":" ","pages":""},"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}
Nature cancerPub Date : 2024-10-01DOI: 10.1038/s43018-024-00830-0
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
{"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":" ","pages":""},"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}
Nature cancerPub Date : 2024-09-27DOI: 10.1038/s43018-024-00812-2
{"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":"5 10","pages":"1455-1456"},"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}
Nature cancerPub Date : 2024-09-26DOI: 10.1038/s43018-024-00824-y
Xinyao Qiu, Tao Zhou, Shuai Li, Jianmin Wu, Jing Tang, Guosheng Ma, Shuai Yang, Ji Hu, Kaiting Wang, Siyun Shen, Hongyang Wang, Lei Chen
{"title":"Spatial single-cell protein landscape reveals vimentinhigh macrophages as immune-suppressive in the microenvironment of hepatocellular carcinoma","authors":"Xinyao Qiu, Tao Zhou, Shuai Li, Jianmin Wu, Jing Tang, Guosheng Ma, Shuai Yang, Ji Hu, Kaiting Wang, Siyun Shen, Hongyang Wang, 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":"5 10","pages":"1557-1578"},"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}
Nature cancerPub Date : 2024-09-20DOI: 10.1038/s43018-024-00828-8
Lea Lemaitre, Nia Adeniji, Akanksha Suresh, Reshma Reguram, Josephine Zhang, Jangho Park, Amit Reddy, Alexandro E. Trevino, Aaron T. Mayer, Anja Deutzmann, Aida S. Hansen, Ling Tong, Vinodhini Arjunan, Neeraja Kambham, Brendan C. Visser, Monica M. Dua, C. Andrew Bonham, Nishita Kothary, H. Blaize D’Angio, Ryan Preska, Yanay Rosen, James Zou, Vivek Charu, Dean W. Felsher, Renumathy Dhanasekaran
{"title":"Spatial analysis reveals targetable macrophage-mediated mechanisms of immune evasion in hepatocellular carcinoma minimal residual disease","authors":"Lea Lemaitre, Nia Adeniji, Akanksha Suresh, Reshma Reguram, Josephine Zhang, Jangho Park, Amit Reddy, Alexandro E. Trevino, Aaron T. Mayer, Anja Deutzmann, Aida S. Hansen, Ling Tong, Vinodhini Arjunan, Neeraja Kambham, Brendan C. Visser, Monica M. Dua, C. Andrew Bonham, Nishita Kothary, H. Blaize D’Angio, Ryan Preska, Yanay Rosen, James Zou, Vivek Charu, Dean W. Felsher, 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":"5 10","pages":"1534-1556"},"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}
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