Heterogeneity and targeted therapy-induced adaptations in lung cancer revealed by longitudinal single-cell RNA sequencing
Heterogeneity and targeted therapy-induced adaptations in lung cancer revealed by longitudinal single-cell RNA sequencing
Lung cancer, the leading cause of cancer mortality, exhibits heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Single-cell RNA sequencing (scRNAseq) of metastatic lung cancer was performed using 44 tumor biopsies obtained longitudinally from 27 patients before and during targeted therapy. Over 20,000 cancer and tumor microenvironment (TME) single-cell profiles exposed a rich and dynamic tumor ecosystem. scRNAseq of cancer cells illuminated targetable oncogenes beyond those detected clinically. Cancer cells surviving therapy as residual disease (RD) expressed an alveolar-regenerative cell signature suggesting a therapy-induced primitive cell state transition, whereas those present at on-therapy progressive disease (PD) upregulated kynurenine, plasminogen, and gap junction pathways. Active T-lymphocytes and decreased macrophages were present at RD and immunosuppressive cell states characterized PD. Biological features revealed by scRNAseq were biomarkers of clinical outcomes in independent cohorts. This study highlights how therapy-induced adaptation of the multi-cellular ecosystem of metastatic cancer shapes clinical outcomes.
Tan Michelle、Maynard Ashley、Thomas Nicholas J.、McCoach Caroline E.、Rotow Julia K.、Harris Lincoln、Haderk Franziska、Zee Alexander、Jahan Thierry、Kratz Johannes R.、Lea Tasha、Jones Kirk、Yamauchi Kevin A.、Naeger David、Gupta Anshal、Jablons David、Neff Norma、Doebele Robert C.、Blakely Collin M.、Bivona Trever G.、Kolli Pallav K.、Tan Weilun、Seeley Eric、Do Hien、Kerr Lucas、Le Daniel D.、Gui Philippe、Yu Elizabeth A.、Weissman Jonathan、Darmanis Spyros、Schenk Erin L.、Sit Rene、Tan Lisa、Urisman Anatoly、Gomez-Sjoberg Rafael、Gubens Matthew、Gonzalez Mayra、Gesthalter Yaron、Wu Wei
肿瘤学生物科学研究方法、生物科学研究技术基础医学
single cell RNA sequencingNSCLCEGFRALKimmune microenvironmentmutationheterogeneitylandscape
Tan Michelle,Maynard Ashley,Thomas Nicholas J.,McCoach Caroline E.,Rotow Julia K.,Harris Lincoln,Haderk Franziska,Zee Alexander,Jahan Thierry,Kratz Johannes R.,Lea Tasha,Jones Kirk,Yamauchi Kevin A.,Naeger David,Gupta Anshal,Jablons David,Neff Norma,Doebele Robert C.,Blakely Collin M.,Bivona Trever G.,Kolli Pallav K.,Tan Weilun,Seeley Eric,Do Hien,Kerr Lucas,Le Daniel D.,Gui Philippe,Yu Elizabeth A.,Weissman Jonathan,Darmanis Spyros,Schenk Erin L.,Sit Rene,Tan Lisa,Urisman Anatoly,Gomez-Sjoberg Rafael,Gubens Matthew,Gonzalez Mayra,Gesthalter Yaron,Wu Wei.Heterogeneity and targeted therapy-induced adaptations in lung cancer revealed by longitudinal single-cell RNA sequencing[EB/OL].(2025-03-28)[2025-05-28].https://www.biorxiv.org/content/10.1101/2019.12.08.868828.点此复制
评论