Archetype tasks link intratumoral heterogeneity to plasticity and cancer hallmarks in small cell lung cancer

Cell Syst. 2022 Sep 21;13(9):690-710.e17. doi: 10.1016/j.cels.2022.07.006. Epub 2022 Aug 17.


Small cell lung cancer (SCLC) tumors comprise heterogeneous mixtures of cell states, categorized into neuroendocrine (NE) and non-neuroendocrine (non-NE) transcriptional subtypes. NE to non-NE state transitions, fueled by plasticity, likely underlie adaptability to treatment and dismal survival rates. Here, we apply an archetypal analysis to model plasticity by recasting SCLC phenotypic heterogeneity through multi-task evolutionary theory. Cell line and tumor transcriptomics data fit well in a five-dimensional convex polytope whose vertices optimize tasks reminiscent of pulmonary NE cells, the SCLC normal counterparts. These tasks, supported by knowledge and experimental data, include proliferation, slithering, metabolism, secretion, and injury repair, reflecting cancer hallmarks. SCLC subtypes, either at the population or single-cell level, can be positioned in archetypal space by bulk or single-cell transcriptomics, respectively, and characterized as task specialists or multi-task generalists by the distance from archetype vertex signatures. In the archetype space, modeling single-cell plasticity as a Markovian process along an underlying state manifold indicates that task trade-offs, in response to microenvironmental perturbations or treatment, may drive cell plasticity. Stifling phenotypic transitions and plasticity may provide new targets for much-needed translational advances in SCLC. A record of this paper's Transparent Peer Review process is included in the supplemental information.

Keywords: RNA velocity; dynamical systems; gene regulatory networks; heterogeneity; phenotypic plasticity; single cell; small cell lung cancer.

Publication types

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

MeSH terms

  • Cell Plasticity
  • Humans
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / pathology
  • Small Cell Lung Carcinoma* / genetics
  • Small Cell Lung Carcinoma* / metabolism
  • Small Cell Lung Carcinoma* / pathology