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

Nemanja Despot Marjanovic; Matan Hofree; Jason E Chan; David Canner; Katherine Wu; Marianna Trakala; Griffin G Hartmann; Olivia C Smith; Jonathan Y Kim; Kelly Victoria Evans; Anna Hudson; Orr Ashenberg; Caroline B M Porter; Alborz Bejnood; Ayshwarya Subramanian; Kenneth Pitter; Yan Yan; Toni Delorey; Devan R Phillips; Nisargbhai Shah; Ojasvi Chaudhary; Alexander Tsankov; Travis Hollmann; Natasha Rekhtman; Pierre P Massion; John T Poirier; Linas Mazutis; Ruifang Li; Joo-Hyeon Lee; Angelika Amon; Charles M Rudin; Tyler Jacks; Aviv Regev; Tuomas Tammela

doi:10.1016/j.ccell.2020.06.012

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

Cancer Cell. 2020 Aug 10;38(2):229-246.e13. doi: 10.1016/j.ccell.2020.06.012. Epub 2020 Jul 23.

Authors

Nemanja Despot Marjanovic¹, Matan Hofree², Jason E Chan³, David Canner⁴, Katherine Wu⁵, Marianna Trakala⁴, Griffin G Hartmann⁵, Olivia C Smith⁶, Jonathan Y Kim⁶, Kelly Victoria Evans⁷, Anna Hudson⁵, Orr Ashenberg², Caroline B M Porter², Alborz Bejnood², Ayshwarya Subramanian², Kenneth Pitter⁸, Yan Yan⁵, Toni Delorey², Devan R Phillips², Nisargbhai Shah⁹, Ojasvi Chaudhary¹⁰, Alexander Tsankov¹¹, Travis Hollmann¹², Natasha Rekhtman¹², Pierre P Massion¹³, John T Poirier¹⁴, Linas Mazutis¹⁰, Ruifang Li¹⁵, Joo-Hyeon Lee⁷, Angelika Amon¹⁶, Charles M Rudin¹⁷, Tyler Jacks¹⁸, Aviv Regev¹⁹, Tuomas Tammela²⁰

Affiliations

¹ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Computational and Systems Biology PhD Program, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
² Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, 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 02139, USA.
⁵ Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁶ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁷ Wellcome - MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
⁸ Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁹ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹⁰ The Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹¹ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹² Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹³ Department of Medicine and Cancer Early Detection and Prevention Initiative, Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
¹⁴ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹⁵ Epigenetics Technology Innovation Lab, Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹⁶ 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 02139, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹⁷ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; The Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹⁸ 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 02139, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: tjacks@mit.edu.
¹⁹ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; 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 02139, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: aregev@broadinstitute.org.
²⁰ Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Cell and Developmental Biology, Weill-Cornell Medical College, New York, NY 10065, USA. Electronic address: tammelat@mskcc.org.

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.

Keywords: cell state transition; chromatin state; differentiation; drug resistance; lung cancer; plasticity; single-cell transcriptomics; tumor evolution; tumor heterogeneity; tumor progression.

Publication types

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

MeSH terms

Animals
Cell Differentiation / genetics
Cell Line, Tumor
Cell Plasticity / genetics*
Cell Proliferation / genetics
Cells, Cultured
Disease Models, Animal
Epithelial Cells / cytology
Epithelial Cells / metabolism*
Epithelial-Mesenchymal Transition / genetics*
Genetic Heterogeneity
Humans
Lung Neoplasms / genetics*
Lung Neoplasms / pathology
Mice
Neoplastic Stem Cells / metabolism*
Single-Cell Analysis / methods
Transcriptome / genetics

Abstract

Publication types

MeSH terms

Grants and funding