@article{5286b0600c1a4a78ae0ce8d9bddfdf50,
title = "Epigenomic State Transitions Characterize Tumor Progression in Mouse Lung Adenocarcinoma",
abstract = "Regulatory networks that maintain functional, differentiated cell states are often dysregulated in tumor development. Here, we use single-cell epigenomics to profile chromatin state transitions in a mouse model of lung adenocarcinoma (LUAD). We identify an epigenomic continuum representing loss of cellular identity and progression toward a metastatic state. We define co-accessible regulatory programs and infer key activating and repressive chromatin regulators of these cell states. Among these co-accessibility programs, we identify a pre-metastatic transition, characterized by activation of RUNX transcription factors, which mediates extracellular matrix remodeling to promote metastasis and is predictive of survival across human LUAD patients. Together, these results demonstrate the power of single-cell epigenomics to identify regulatory programs to uncover mechanisms and key biomarkers of tumor progression.",
keywords = "cancer, epigenomics, epithelial-to-mesenchymal transition, metastasis, non-small cell lung cancer, single cell",
author = "LaFave, {Lindsay M.} and Kartha, {Vinay K.} and Sai Ma and Kevin Meli and {Del Priore}, Isabella and Caleb Lareau and Santiago Naranjo and Westcott, {Peter M.K.} and Duarte, {Fabiana M.} and Venkat Sankar and Zachary Chiang and Alison Brack and Travis Law and Haley Hauck and Annalisa Okimoto and Aviv Regev and Buenrostro, {Jason D.} and Tyler Jacks",
note = "Funding Information: We thank the members of the Jacks and Buenrostro labs for their critical reading of the manuscript and helpful discussions, including Tongtong Zhao, Rodrigo Romero, Leanne Li, Alex Jaeger, Amanda Cruz, and Carla Concepcion. We also thank Carman Li and Vasilena Gocheva for helpful conversations. We thank Amir Giladi for help with the interpretation of the lung development data. We thank Paul Chamberlain for the support on tail vein assays. We thank Tuomas Tammela for the Aiforia algorithm. We thank the Histology and Flow Cytometry cores at the Swanson Biotechnology Center, the Walk-up sequencing core at the Broad Institute, and the Bauer sequencing core at Harvard. We are grateful to the Zhang lab for providing Tn5. L.M.L. is supported by the Damon Runyon Cancer Foundation postdoctoral fellowship. J.D.B. acknowledges support from the Allen Distinguished Investigator Program, through The Paul G. Allen Frontiers Group . T.J. is a Howard Hughes Medical Institute Investigator and a Daniel K. Ludwig Scholar. This work was supported in part by grant PO1-CA42063 from the National Institutes of Health and partially by Cancer Center Support (core) grant P30-CA14051 from the National Cancer Institute . Funding Information: We thank the members of the Jacks and Buenrostro labs for their critical reading of the manuscript and helpful discussions, including Tongtong Zhao, Rodrigo Romero, Leanne Li, Alex Jaeger, Amanda Cruz, and Carla Concepcion. We also thank Carman Li and Vasilena Gocheva for helpful conversations. We thank Amir Giladi for help with the interpretation of the lung development data. We thank Paul Chamberlain for the support on tail vein assays. We thank Tuomas Tammela for the Aiforia algorithm. We thank the Histology and Flow Cytometry cores at the Swanson Biotechnology Center, the Walk-up sequencing core at the Broad Institute, and the Bauer sequencing core at Harvard. We are grateful to the Zhang lab for providing Tn5. L.M.L. is supported by the Damon Runyon Cancer Foundation postdoctoral fellowship. J.D.B. acknowledges support from the Allen Distinguished Investigator Program, through The Paul G. Allen Frontiers Group. T.J. is a Howard Hughes Medical Institute Investigator and a Daniel K. Ludwig Scholar. This work was supported in part by grant PO1-CA42063 from the National Institutes of Health and partially by Cancer Center Support (core) grant P30-CA14051 from the National Cancer Institute. Conceptualization, L.M.L. J.D.B. and T.J.; Methodology, L.M.L. V.K.K. S.M. V.S. and J.D.B.; Validation, L.M.L. S.M. V.K.K. K.M. I.D.P. F.M.D. and Z.C.; Formal Analysis, S.M. V.K.K. C.L. V.S. P.W. Z.C. and J.D.B.; Investigation, L.M.L. S.M. V.K.K. K.M. I.D.P C.L. A.B. V.S. T.L. H.H. A.O. and I.D.P.; Resources, S.N. and C.L.; Data Curation, L.M.L, V.K.K. S.M. K.M. I.D.P. and J.D.B.; Writing – Original Draft, L.M.L. and J.D.B.; Writing – Review & Editing, All authors; Visualization, L.M.L. V.K.K. S.M. and J.D.B.; Supervision, A.R. J.D.B. and T.J. Funding Acquisition, L.M.L. J.D.B. and T.J. T.J. is a member of the Board of Directors of Amgen and Thermo Fisher Scientific. He is also 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. None of these affiliations represent a conflict of interest with respect to the design or execution of this study or interpretation of data presented in this manuscript. T.J. laboratory currently also receives funding from the Johnson & Johnson Lung Cancer Initiative and The Lustgarten Foundation for Pancreatic Cancer Research, but this funding did not support the research described in this manuscript. J.D.B. holds patents related to ATAC-seq and single-cell ATAC-seq and serves on the Scientific Advisory Board of CAMP4 Therapeutics and seqWell. A.R. is a co-founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas, and an SAB member of Thermo Fisher Scientific, Syros Pharmaceuticals, Asimov, and Neogene Therapeutics. Funding Information: T.J. is a member of the Board of Directors of Amgen and Thermo Fisher Scientific. He is also 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. None of these affiliations represent a conflict of interest with respect to the design or execution of this study or interpretation of data presented in this manuscript. T.J. laboratory currently also receives funding from the Johnson & Johnson Lung Cancer Initiative and The Lustgarten Foundation for Pancreatic Cancer Research, but this funding did not support the research described in this manuscript. J.D.B. holds patents related to ATAC-seq and single-cell ATAC-seq and serves on the Scientific Advisory Board of CAMP4 Therapeutics and seqWell. A.R. is a co-founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas, and an SAB member of Thermo Fisher Scientific, Syros Pharmaceuticals, Asimov, and Neogene Therapeutics. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = aug,
day = "10",
doi = "10.1016/j.ccell.2020.06.006",
language = "English (US)",
volume = "38",
pages = "212--228.e13",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "2",
}
