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 ShahOjasvi 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

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

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. Cellular states capable of promoting tumor progression and resisting therapies exist in heterogeneous tumors. Marjanovic et al. discover that a high-plasticity cell state common to mouse and human lung tumors drives cellular heterogeneity, is highly tumorigenic and drug resistant, and associates with poor patient prognosis.

Original languageEnglish
Pages (from-to)229-246.e13
JournalCancer Cell
Volume38
Issue number2
DOIs
StatePublished - 10 Aug 2020

Keywords

  • cell state transition
  • chromatin state
  • differentiation
  • drug resistance
  • lung cancer
  • plasticity
  • single-cell transcriptomics
  • tumor evolution
  • tumor heterogeneity
  • tumor progression

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