Abstract
It is increasingly apparent that tumors represent dynamic structures in which cell populations, defined by genetic, epigenetic and non-genetic variation, compete for space and resources, while attempting to evade host defenses, resist therapeutic interventions and colonize new environments. Yet, the extent of this intratumoral genetic heterogeneity and the rules governing this ecosystem remain largely unknown. Using a large inventory of patient-derived xenograft models and an ex vivo culture system that maintains the transcriptional fidelity of the primary tumors, we have interrogated small cell lung cancer (SCLC) as a tractable model system for studying tumor evolution. In the process, we have identified at least three morphologically distinct intratumoral subpopulations across several samples: (i) suspended aggregates of small cells (neuroendocrine or NE), (ii) larger, pleomorphic cells with visible cytoplasm and spindle-like membrane extensions growing as a monolayer (mesenchymal or MS) and (iii) pre-suspension aggregates that are nested above mesenchymal-like cells (proneural or PN). Moreover, we have shown that these subpopulations are functionally distinct as measured by cellular proliferation, migration/invasion ability and sensitivity to chemotherapy/radiation. Intriguingly, distinct inter-tumoral transcriptional states assembled from earlier analyses of SCLC gene expression values across 53 and 71 cell lines and primary tumors, respectively, were preserved in the three intratumoral subpopulations within our examined SCLC lines. The proportion of each well-defined subpopulation varied across samples, suggesting sample-specific fractional setpoints. Finally, we have identified transcription factors that function as central nodes in the gene expression networks of each population and have used computational tools to nominate and functionally confirm biological processes within each population. Namely, we have shown that ASCL1 marks the rapidly proliferating NE population, NEUROD1 marks the primitive PN population and YAP1 marks the slow-growing MS population. We posit that understanding the SCLC ecosystem will provide substantial insight into its biological and clinical behavior and advance therapeutic possibilities in this recalcitrant disease.
Citation Format: Craig D. Peacock, Priyanka Gopal, Aaron Petty, Kevin Rogacki, Mohamed E. Abazeed. Intratumoral heterogeneity in small cell carcinoma of the lung: An evolutionary and ecologic process [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1186.
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