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Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing
Open accessAbstract
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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Metadata
- Authors
- Maynard, A., McCoach, C. E., Rotow, J. K., Harris, L., Haderk, F., Kerr, D. L., Yu, E. A., Schenk, E. L., Tan, W., Zee, A., Tan, M., Gui, P., Lea, T., Wu, W., Urisman, A., Jones, K., Sit, R., Kolli, P. K., Seeley, E., Gesthalter, Y., Le, D. D., Yamauchi, K. A., Naeger, D. M., Bandyopadhyay, S., Shah, K., Cech, L., Thomas, N. J., Gupta, A., Gonzalez, M., Do, H., Tan, L., Bacaltos, B., Gomez-Sjoberg, R., Gubens, M., Jahan, T., Kratz, J. R., Jablons, D., Neff, N., Doebele, R. C., Weissman, J., Blakely, C. M., Darmanis, S., & Bivona, T. G.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 182
- Issue
- 5
- Pages
- 1232-1251.e22
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W3078555423
- Cited by
- 685
- References
- 155
- FWCI
- 24.69
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Maynard, A., McCoach, C. E., Rotow, J. K., Harris, L., Haderk, F., Kerr, D. L., Yu, E. A., Schenk, E. L., Tan, W., Zee, A., Tan, M., Gui, P., Lea, T., Wu, W., Urisman, A., Jones, K., Sit, R., Kolli, P. K., Seeley, E., . . . Bivona, T. G. (2020). Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing. Cell. https://doi.org/10.1016/j.cell.2020.07.017
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