Pub Date : 2025-09-30DOI: 10.1038/s41422-025-01180-x
Xiaoling Li, Eric E. Gardner, Sonia Molina-Pinelo, Clare Wilhelm, Ping Mu, Álvaro Quintanal-Villalonga
Lineage plasticity, the ability of cells to transition to an alternative phenotype as a means for adaptation, is an increasingly recognized mechanism of tumor evolution and a driver of resistance to anticancer therapies. The most extensively described clinical settings impacted by such molecular phenomena include neuroendocrine transformation in androgen receptor-dependent prostate adenocarcinoma, and adenocarcinoma-to-neuroendocrine and adenocarcinoma-to-squamous transdifferentiation in epidermal growth factor receptor-driven lung adenocarcinoma, affecting 10%–20% of patients treated with targeted therapy. Recent analyses of human tumor samples and in vivo models of histological transformation have led to insights into the biology of lineage plasticity, including biomarkers predictive of high risk of transformation. However, no clinically available therapies aimed to prevent or revert plasticity are currently available. In the present review, we will provide a biological and therapeutic overview of the current understanding of common and divergent molecular drivers of neuroendocrine and squamous transdifferentiation in tumors from different origins, including descriptive analysis of previously known and recently described molecular events associated with histological transformation, and propose evidence-based alternative models of transdifferentiation. A clear definition of the commonalities and differences of transforming tumors in different organs and to different histological fates will be important to translate molecular findings to the clinical setting.
{"title":"Lineage plasticity and histological transformation: tumor histology as a spectrum","authors":"Xiaoling Li, Eric E. Gardner, Sonia Molina-Pinelo, Clare Wilhelm, Ping Mu, Álvaro Quintanal-Villalonga","doi":"10.1038/s41422-025-01180-x","DOIUrl":"10.1038/s41422-025-01180-x","url":null,"abstract":"Lineage plasticity, the ability of cells to transition to an alternative phenotype as a means for adaptation, is an increasingly recognized mechanism of tumor evolution and a driver of resistance to anticancer therapies. The most extensively described clinical settings impacted by such molecular phenomena include neuroendocrine transformation in androgen receptor-dependent prostate adenocarcinoma, and adenocarcinoma-to-neuroendocrine and adenocarcinoma-to-squamous transdifferentiation in epidermal growth factor receptor-driven lung adenocarcinoma, affecting 10%–20% of patients treated with targeted therapy. Recent analyses of human tumor samples and in vivo models of histological transformation have led to insights into the biology of lineage plasticity, including biomarkers predictive of high risk of transformation. However, no clinically available therapies aimed to prevent or revert plasticity are currently available. In the present review, we will provide a biological and therapeutic overview of the current understanding of common and divergent molecular drivers of neuroendocrine and squamous transdifferentiation in tumors from different origins, including descriptive analysis of previously known and recently described molecular events associated with histological transformation, and propose evidence-based alternative models of transdifferentiation. A clear definition of the commonalities and differences of transforming tumors in different organs and to different histological fates will be important to translate molecular findings to the clinical setting.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 11","pages":"803-823"},"PeriodicalIF":25.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01180-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-29DOI: 10.1038/s41422-025-01185-6
Qihang Zhong, Dandan Chen, Jinkun Xu, Yao Li, Wanqiong Yuan, Yan Meng, Qi Wen, Qiwei Ye, Guopeng Wang, Kexin Pan, Chunli Song, Lin Tao, Jie Qiao, Jing Hang
Pub Date : 2025-09-19DOI: 10.1038/s41422-025-01183-8
Xiao-Peng Han, Ming Rao, Yu Chang, Jun-Yan Zhu, Jun Cheng, Yu-Ting Li, Wu Qiong, Si-Chao Ye, Qiurong Zhang, Shao-Qing Zhang, Ling-Ling Chen, Fajian Hou, Jin Zhong, Jiaquan Liu
MDA5 is a RIG-I-like receptor (RLR) that recognizes viral double-stranded RNA (dsRNA) to initiate the innate immune response. Its activation requires filament formation along the dsRNA, which triggers the oligomerization of N-terminal caspase activation and recruitment domains. The ATPase activity of MDA5 is critical for immune homeostasis, likely by regulating filament assembly. However, the molecular basis underlying this process remains poorly understood. Here, we show that MDA5 operates as an ATP-hydrolysis-driven motor that translocates along dsRNA in a one-dimensional (1D) manner. Multiple MDA5 motors can cooperatively load onto a single dsRNA, but their movements rarely synchronize, inhibiting spontaneous filament formation and activation. LGP2, a key regulator of MDA5 signaling, recognizes MDA5 motors and blocks their movement, thereby promoting filament assembly through a translocation-directed mechanism. This unique assembly strategy underscores the role of 1D motion in higher-order protein oligomerization and reveals a novel mechanism for maintaining immune homeostasis.
{"title":"ATP-dependent one-dimensional movement maintains immune homeostasis by suppressing spontaneous MDA5 filament assembly","authors":"Xiao-Peng Han, Ming Rao, Yu Chang, Jun-Yan Zhu, Jun Cheng, Yu-Ting Li, Wu Qiong, Si-Chao Ye, Qiurong Zhang, Shao-Qing Zhang, Ling-Ling Chen, Fajian Hou, Jin Zhong, Jiaquan Liu","doi":"10.1038/s41422-025-01183-8","DOIUrl":"10.1038/s41422-025-01183-8","url":null,"abstract":"MDA5 is a RIG-I-like receptor (RLR) that recognizes viral double-stranded RNA (dsRNA) to initiate the innate immune response. Its activation requires filament formation along the dsRNA, which triggers the oligomerization of N-terminal caspase activation and recruitment domains. The ATPase activity of MDA5 is critical for immune homeostasis, likely by regulating filament assembly. However, the molecular basis underlying this process remains poorly understood. Here, we show that MDA5 operates as an ATP-hydrolysis-driven motor that translocates along dsRNA in a one-dimensional (1D) manner. Multiple MDA5 motors can cooperatively load onto a single dsRNA, but their movements rarely synchronize, inhibiting spontaneous filament formation and activation. LGP2, a key regulator of MDA5 signaling, recognizes MDA5 motors and blocks their movement, thereby promoting filament assembly through a translocation-directed mechanism. This unique assembly strategy underscores the role of 1D motion in higher-order protein oligomerization and reveals a novel mechanism for maintaining immune homeostasis.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 11","pages":"900-912"},"PeriodicalIF":25.9,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01183-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-12DOI: 10.1038/s41422-025-01167-8
Peixing Wan, Swati Choksi, Yeon-Ji Park, Xin Chen, Jiong Yan, Sahar Foroutannejad, Zhaoshan Liu, Jichun Chen, Ross Lake, Chengyu Liu, Zheng-Gang Liu
Tissue factor (TF) is a cell surface protein critical for normal hemostasis and pathological thrombosis. Necroptosis is a form of regulated necrosis associated with different diseases. Here, we reported the identification of the first functional soluble tissue factor (sTF) in mediating blood coagulation, shed from the membrane full-length TF (flTF) by proteases, ADAMs, during necroptosis. By generating sTF-specific antibody and transgenic mice carrying knockin mutations at the ADAM cleavage site of TF (T211V212 mutated to E211E212), we demonstrated that this sTF is responsible for necroptosis-related thrombosis in inflammation and viral infection mouse models. Importantly, we showed that eliminating necroptosis or the cleavage of the flTF blocked the production of sTF and prevented thrombosis in mice. We also detected sTF in the plasma of human COVID-19 patients and showed that SARS-CoV-2 pseudovirus induced sTF production. Our findings demonstrated that the sTF plays a major role in thrombosis under necroptosis-related pathological conditions and provided a diagnostic marker and potential therapies for treating thrombosis without affecting hemostasis.
{"title":"Soluble tissue factor generated by necroptosis-triggered shedding is responsible for thrombosis","authors":"Peixing Wan, Swati Choksi, Yeon-Ji Park, Xin Chen, Jiong Yan, Sahar Foroutannejad, Zhaoshan Liu, Jichun Chen, Ross Lake, Chengyu Liu, Zheng-Gang Liu","doi":"10.1038/s41422-025-01167-8","DOIUrl":"10.1038/s41422-025-01167-8","url":null,"abstract":"Tissue factor (TF) is a cell surface protein critical for normal hemostasis and pathological thrombosis. Necroptosis is a form of regulated necrosis associated with different diseases. Here, we reported the identification of the first functional soluble tissue factor (sTF) in mediating blood coagulation, shed from the membrane full-length TF (flTF) by proteases, ADAMs, during necroptosis. By generating sTF-specific antibody and transgenic mice carrying knockin mutations at the ADAM cleavage site of TF (T211V212 mutated to E211E212), we demonstrated that this sTF is responsible for necroptosis-related thrombosis in inflammation and viral infection mouse models. Importantly, we showed that eliminating necroptosis or the cleavage of the flTF blocked the production of sTF and prevented thrombosis in mice. We also detected sTF in the plasma of human COVID-19 patients and showed that SARS-CoV-2 pseudovirus induced sTF production. Our findings demonstrated that the sTF plays a major role in thrombosis under necroptosis-related pathological conditions and provided a diagnostic marker and potential therapies for treating thrombosis without affecting hemostasis.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 11","pages":"840-858"},"PeriodicalIF":25.9,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01167-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：