Maynard, Ashley and McCoach, Caroline E and Rotow, Julia K and Harris, Lincoln and Haderk, Franziska and Kerr, D Lucas and Elizabeth, A Yu and Schenk, Erin L and Tan, Weilun and Zee, Alexander and others
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 ontherapy 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.