Emergence of a High-Plasticity Cell State during Lung Cancer Evolution.

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.This work was supported by the Transcend Program and Janssen Pharmaceuticals, the Howard Hughes Medical Institute, and, in part, by the NIH/NCI Cancer Center Support Grants P30-CA08748 (MSKCC) and P30-CA14051 (Koch Institute). T.T. is supported by American Cancer Society, Rita Allen, Josie Robertson Scholar, and V Foundation Scholarships and the American Association for Cancer Research Next Generation Transformative Research Award; the American Lung Association; the Stanley and Fiona Druckenmiller Center for Lung Cancer Research; and NCI-CA187317. T.J. is supported by NCI-PO1CA42063. A.R. is supported by the Klarman Cell Observatory. J.E.C is supported by the MSK T32 Investigational Cancer Therapeutics Training Program Grant (NIH MSK ICTTP T32-CA009207). P.P.M. is supported by NCI-CA196405. L.M. is supported by The Alan and Sandra Gerry Foundation. We acknowledge the use of the Integrated Genomics Operation Core, funded by CCSG P30-CA08748, Cycle for Survival, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology at MSKCC; the Flow Cytometry and Histology Core Facilities at the Swanson Biotechnology Center at the Koch Institute; and the MIT Bio-Micro Center. A.R., T.J.and A.A. are Howard Hughes Medical Institute Investigators; T.J. is a David H. Koch Professor of Biology, and a Daniel K. Ludwig Scholar