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Updated: May 4, 2026
Targeted RNA Sequencing Assay to Characterize Gene Expression and Genomic Alterations
Published on: August 4, 2016
Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing
Ashley Maynard1, Caroline E McCoach2, Julia K Rotow3
1Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
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.
Insights
Metastatic lung cancer adapts to therapy through cellular changes, impacting treatment outcomes. Understanding these adaptations via single-cell RNA sequencing (scRNA-seq) reveals new therapeutic targets and biomarkers.
Area of Science:
- Oncology
- Genomics
- Immunology
Background:
- Lung cancer is a leading cause of cancer mortality.
- Tumor heterogeneity complicates treatment and understanding.
- Metastatic lung cancer requires advanced analysis techniques.
Purpose of the Study:
- To investigate the cellular and molecular adaptations of metastatic lung cancer during targeted therapy.
- To identify novel therapeutic targets and biomarkers through single-cell analysis.
- To understand the role of the tumor microenvironment (TME) in therapy resistance.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) was performed on 49 clinical biopsies from 30 patients.
- Analysis included cancer cells and tumor microenvironment (TME) components.
- scRNA-seq data was correlated with clinical outcomes in independent cohorts.
Main Results:
- Over 20,000 single-cell profiles revealed a dynamic tumor ecosystem.
- Residual disease (RD) cells showed an alveolar-regenerative signature, suggesting cell-state transitions.
- Progressive disease (PD) cells upregulated kynurenine, plasminogen, and gap-junction pathways.
- RD was associated with active T-lymphocytes and decreased macrophages, while PD showed immunosuppressive states.
Conclusions:
- Therapy-induced adaptations in the multi-cellular ecosystem of metastatic lung cancer significantly shape clinical outcomes.
- scRNA-seq identified targetable oncogenes and biomarkers beyond clinical detection.
- Understanding these dynamic changes is crucial for improving lung cancer therapy.
