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Mechanobiology

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

AUTHORS

Groves SMSarah M , Ildefonso GVGeena V , McAtee COCaitlin O , Ozawa PMMPatricia M M , Ireland ASAbbie S , Stauffer PEPhilip E , Wasdin PTPerry T , Huang XXiaomeng , Qiao YYi , Lim JSJing Shan , Bader JJackie , Liu QQi , Simmons AJAlan J , Lau KSKen S , Iams WTWade T , Hardin DPDoug P , Saff EBEdward B , Holmes WRWilliam R , Tyson DRDarren R , Lovly CMChristine M , Rathmell JCJeffrey C , Marth GGabor , Sage JJulien , Oliver TGTrudy G , Weaver AMAlissa M , Quaranta VVito . Cell systems. 2022 08 15; ().

ABSTRACT

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.