1. Emergence of a High-Plasticity Cell State during Lung Cancer Evolution.
- Author
-
Marjanovic ND, Hofree M, Chan JE, Canner D, Wu K, Trakala M, Hartmann GG, Smith OC, Kim JY, Evans KV, Hudson A, Ashenberg O, Porter CBM, Bejnood A, Subramanian A, Pitter K, Yan Y, Delorey T, Phillips DR, Shah N, Chaudhary O, Tsankov A, Hollmann T, Rekhtman N, Massion PP, Poirier JT, Mazutis L, Li R, Lee JH, Amon A, Rudin CM, Jacks T, Regev A, and Tammela T
- Subjects
- Animals, Cell Differentiation genetics, Cell Line, Tumor, Cell Proliferation genetics, Cells, Cultured, Disease Models, Animal, Epithelial Cells cytology, Genetic Heterogeneity, Humans, Lung Neoplasms pathology, Mice, Single-Cell Analysis methods, Transcriptome genetics, Cell Plasticity genetics, Epithelial Cells metabolism, Epithelial-Mesenchymal Transition genetics, Lung Neoplasms genetics, Neoplastic Stem Cells metabolism
- Abstract
Tumor evolution from a single cell into a malignant, heterogeneous tissue remains poorly understood. Here, we profile single-cell transcriptomes of genetically engineered mouse lung tumors at seven stages, from pre-neoplastic hyperplasia to adenocarcinoma. The diversity of transcriptional states increases over time and is reproducible across tumors and mice. Cancer cells progressively adopt alternate lineage identities, computationally predicted to be mediated through a common transitional, high-plasticity cell state (HPCS). Accordingly, HPCS cells prospectively isolated from mouse tumors and human patient-derived xenografts display high capacity for differentiation and proliferation. The HPCS program is associated with poor survival across human cancers and demonstrates chemoresistance in mice. Our study reveals a central principle underpinning intra-tumoral heterogeneity and motivates therapeutic targeting of the HPCS., Competing Interests: Declaration of Interests T.J. is a member of the Board of Directors of Amgen and Thermo Fisher Scientific, and a co-Founder of Dragonfly Therapeutics and T2 Biosystems. T.J. serves on the Scientific Advisory Board of Dragonfly Therapeutics, SQZ Biotech, and Skyhawk Therapeutics. T.J. also received funding from Calico and currently receives funding from Johnson & Johnson, but this funding did not support the research described in this manuscript. A.R. is a co-founder and equity holder in Celsius Therapeutics and a SAB member for Thermo Fisher, Asimov, Neogene Therapeutics, and Syros Pharmaceuticals, and an equity holder of Immunitas Therapeutics. C.M.R. serves on the SAB of Bridge Medicines and Harpoon Therapeutics, and has consulted regarding oncology drug development with AbbVie, Amgen, Ascentage, Bicycle, Celgene, Daiichi Sankyo, Genentech, Ipsen, Loxo, Pharmamar, and Vavotek. None of the affiliations listed above represent a conflict of interest with the design or execution of this study or interpretation of data presented in this manuscript. Other authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF