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

Summary

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.

Graphical Abstract

Highlights

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  scRNA-seq is feasible in metastatic human NSCLCs and reveals a rich tumor ecosystem

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  Individual tumors and cancer cells exhibit substantial molecular diversity

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  Cancer and tumor microenvironment cells exhibit marked therapy-induced plasticity

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  scRNA-seq of metastatic NSCLCs unveils new opportunities to improve clinical outcomes

Abstract

Analysis of metastatic lung cancer biopsies before and after targeted therapy reveals molecular and immune adaptations that shape clinical outcomes.