Cellular plasticity gives rise to phenotypic equilibrium in small cell lung carcinoma

Small cell lung carcinoma (SCLC) is one of the most intractable human cancers to cure. It is an aggressive tumorcharacterized by rapid growth, metastatic progression, and initial response followed by almost invariableresistance to therapy. Studies to date have not resolved the extent that diverse genetic and epigenetic programsdrive SCLC and contribute to its lethality. We combined one of the largest and most diverse inventories ofpatient-derived xenograft models of SCLC globally with an ex vivo culture system that maintainstranscriptional fidelity with matched primary SCLC tumor to identify distinct and dynamic phenotypic states thatdiffer in functional attributes within individual tumors. We show, for the first time, that human SCLC tumors displaydistinctive equilibria in the proportion of cells in various transcriptional and phenotypic states that are regulatedby plasticity with very little hierarchy. We also show that standard of care anticancer therapies in this diseasepreferentially kill specific cancer cell states. In this proposal, we posit that understanding the facets of SCLC’sintratumoral heterogeneity will: 1) contribute to our understanding of a poorly characterized aspect of cancerheterogeneity; 2) reveal how stochasticity and/or ecological cues in single-cell behaviors promote phenotypicequilibrium in cancer populations; 3) provide insight into the biological and clinical behavior of SCLC; and 4)advance desperately needed new therapeutic strategies of epigenetic reprogramming in this recalcitrant disease.Our team of investigators have content expertise in several computational, experimental, and translationalmethods pertinent to this proposal including human-derived in vivo and ex vivo model systems, single-cell RNAsequencing, bulk genetic and expression analysis, single cell fluorescence tracing, and mathematical andstatistical modeling. Our integrative approach is poised to formulate and validate a unified model of cellular statesand program diversity in SCLC. If successful, the characterization of malignant cell ontogenic programs (SA1),their plasticity (SA2), and the advancement of new therapies designed to combat plasticity by epigeneticreprogramming (SA3) will create a new scientific canvas for the study of this highly lethal disease.