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

Ashley Maynard(Chan Zuckerberg Initiative (United States)), Caroline E. McCoach(University of California, San Francisco), Julia Rotow(Dana-Farber Cancer Institute), Lincoln Harris(Chan Zuckerberg Initiative (United States)), Franziska Haderk(University of California, San Francisco), D. Lucas Kerr(University of California, San Francisco), Elizabeth A. Yu(University of California, San Francisco), Erin L. Schenk(University of Colorado Anschutz Medical Campus), Weilun Tan(Chan Zuckerberg Initiative (United States)), Alexander Zee(University of California, Santa Cruz), Michelle Tan(Chan Zuckerberg Initiative (United States)), Philippe Gui(University of California, San Francisco), Tasha Lea(University of California, San Francisco), Wei Wu(University of California, San Francisco), Anatoly Urisman(University of California, San Francisco), Kirk D. Jones(University of California, San Francisco), Rene Sit(Chan Zuckerberg Initiative (United States)), K. Kolli(University of California, San Francisco), Eric J. Seeley(University of California, San Francisco), Yaron Gesthalter(University of California, San Francisco), Daniel D. Le(Chan Zuckerberg Initiative (United States)), Kevin A. Yamauchi(Chan Zuckerberg Initiative (United States)), David M. Naeger(University of Colorado Hospital), Sourav Bandyopadhyay(University of California, San Francisco), Khyati N. Shah(University of California, San Francisco), Lauren Čech(University of California, San Francisco), Nicholas J. Thomas(University of California, San Francisco), Anshal Gupta(University of California, San Francisco), Mayra Gonzalez(University of California, San Francisco), Hien Do(University of California, San Francisco), Lisa Tan(University of California, San Francisco), Bianca Bacaltos(University of California, San Francisco), Rafael Gómez-Sjöberg(Chan Zuckerberg Initiative (United States)), Matthew A. Gubens(University of California, San Francisco), Thierry Jahan(University of California, San Francisco), Johannes R. Kratz(University of California, San Francisco), David M. Jablons(University of California, San Francisco), Norma Neff(Chan Zuckerberg Initiative (United States)), Robert C. Doebele(University of Colorado Anschutz Medical Campus), Jonathan S. Weissman(Howard Hughes Medical Institute), Collin M. Blakely(University of California, San Francisco), Spyros Darmanis(Chan Zuckerberg Initiative (United States)), Trever G. Bivona(University of California, San Francisco)
Cell
August 20, 2020
10.1016/j.cell.2020.07.017
Cited by 688Open Access
Full Text

Abstract

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.

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