Journal
CANCER CELL
Volume 38, Issue 2, Pages 229-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2020.06.012
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Categories
Funding
- Transcend Program
- Janssen Pharmaceuticals
- Howard Hughes Medical Institute
- NIH/NCI Cancer Center [P30-CA08748, P30-CA14051]
- American Cancer Society
- Rita Allen, Josie Robertson, and V Foundation Scholarships
- American Association for Cancer Research Next Generation Transformative Research Award
- American Lung Association
- Stanley and Fiona Druckenmiller Center for Lung Cancer Research
- Klarman Cell Observatory
- MSK T32 Investigational Cancer Therapeutics Training Program Grant [NIH MSK ICTTP T32-CA009207]
- National Science Foundation
- Alan and Sandra Gerry Foundation
- CCSG [P30-CA08748]
- Cycle for Survival
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology at MSKCC
- Flow Cytometry and Histology Core Facilities at the Swanson Biotechnology Center at the Koch Institute
- MIT Bio-Micro Center
- [P01CA42063]
- [NCI-CA187317]
- [P01-CA42063]
- [NCI-CA196405]
- BBSRC [1943428] Funding Source: UKRI
- MRC [MC_PC_17230] Funding Source: UKRI
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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.
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