Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing
Ashley Maynard, Caroline E. McCoach, Julia Rotow, Lincoln Harris, Franziska Haderk, D. Lucas Kerr, Elizabeth A. Yu, Erin L. Schenk, Weilun Tan, Alexander Zee, Michelle Tan, Philippe Gui, Tasha Lea, Wei Wu, Anatoly Urisman, Kirk D. Jones, Rene Sit, K. Kolli, Eric J. Seeley, Yaron Gesthalter, Daniel D. Le, Kevin A. Yamauchi, David M. Naeger, Sourav Bandyopadhyay, Khyati N. Shah, Lauren Čech, Nicholas J. Thomas, Anshal Gupta, Mayra Gonzalez, Hien Do, Lisa Tan, Bianca Bacaltos, Rafael Gómez-Sjöberg, Matthew A. Gubens, Thierry Jahan, Johannes R. Kratz, David M. Jablons, Norma Neff, Robert C. Doebele, Jonathan S. Weissman, Collin M. Blakely, Spyros Darmanis, Trever G. Bivona
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.