Epigenomic State Transitions Characterize Tumor Progression in Mouse Lung Adenocarcinoma

Lindsay M LaFave; Vinay K Kartha; Sai Ma; Kevin Meli; Isabella Del Priore; Caleb Lareau; Santiago Naranjo; Peter M K Westcott; Fabiana M Duarte; Venkat Sankar; Zachary Chiang; Alison Brack; Travis Law; Haley Hauck; Annalisa Okimoto; Aviv Regev; Jason D Buenrostro; Tyler Jacks

doi:10.1016/j.ccell.2020.06.006

Epigenomic State Transitions Characterize Tumor Progression in Mouse Lung Adenocarcinoma

Cancer Cell. 2020 Aug 10;38(2):212-228.e13. doi: 10.1016/j.ccell.2020.06.006. Epub 2020 Jul 23.

Authors

Lindsay M LaFave¹, Vinay K Kartha², Sai Ma³, Kevin Meli⁴, Isabella Del Priore⁴, Caleb Lareau⁵, Santiago Naranjo⁴, Peter M K Westcott⁴, Fabiana M Duarte², Venkat Sankar⁶, Zachary Chiang², Alison Brack², Travis Law⁷, Haley Hauck⁴, Annalisa Okimoto⁴, Aviv Regev⁸, Jason D Buenrostro⁹, Tyler Jacks¹⁰

Affiliations

¹ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
² Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
³ Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
⁴ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
⁶ Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
⁷ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁸ Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: jason_buenrostro@harvard.edu.
¹⁰ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: tjacks@mit.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / genetics*
Adenocarcinoma / metabolism
Adenocarcinoma / pathology
Animals
Cell Line, Tumor
Disease Models, Animal*
Disease Progression
Epigenomics / methods*
Gene Expression Profiling / methods
Gene Expression Regulation, Neoplastic*
Humans
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Signal Transduction / genetics
Single-Cell Analysis / methods

Abstract

Publication types

MeSH terms

Grants and funding