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Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing

Authors: Maynard, Ashley; McCoach, Caroline E.; Rotow, Julia K.; Harris, Lincoln; Haderk, Franziska; Kerr, D. Lucas; Yu, Elizabeth A.; Schenk, Erin L.; Tan, Weilun; Zee, Alexander; Tan, Michelle; Gui, Philippe; Lea, Tasha; Wu, Wei; Urisman, Anatoly; Jones, Kirk; Sit, Rene; Kolli, Pallav K.; Seeley, Eric; Gesthalter, Yaron; Le, Daniel D.; Yamauchi, Kevin A.; Naeger, David M.; Bandyopadhyay, Sourav; Shah, Khyati; Cech, Lauren; Thomas, Nicholas J.; Gupta, Anshal; Gonzalez, Mayra; Do, Hien; Tan, Lisa; Bacaltos, Bianca; Gomez-Sjoberg, Rafael; Gubens, Matthew; Jahan, Thierry; Kratz, Johannes R.; Jablons, David; Neff, Norma; Doebele, Robert C.; Weissman, Jonathan; Blakely, Collin M.; Darmanis, Spyros; Bivona, Trever G.

Online: https://www.cell.com/cell/abstract/S0092-8674(20)30882-5

Issue: Cell . 2020 Sep 3;182(5):1232-1251.e22.


Lung cancer, the leading cause of cancer mortality, exhibits heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Single-cell RNA sequencing (scRNA-seq) of metastatic lung cancer was performed using 49 clinical biopsies obtained from 30 patients before and during targeted therapy. Over 20,000 cancer and tumor microenvironment (TME) single-cell profiles exposed a rich and dynamic tumor ecosystem. scRNA-seq 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 scRNA-seq 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.