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

ABSTRACT
Small cell lung carcinoma (SCLC) is one of the most intractable human cancers to cure. It is an aggressive tumor
characterized by rapid growth, metastatic progression, and initial response followed by almost invariable
resistance to therapy. Studies to date have not resolved the extent that diverse genetic and epigenetic programs
drive SCLC and contribute to its lethality. We combined one of the largest and most diverse inventories of
patient-derived xenograft models of SCLC globally with an ex vivo culture system that maintains
transcriptional fidelity with matched primary SCLC tumor to identify distinct and dynamic phenotypic states that
differ in functional attributes within individual tumors. We show that human SCLC tumors display distinctive
equilibria in the proportion of cells in various phenotypic (not merely transcriptional) states. We also show that
SCLC states are highly regulated by multivalent cellular plasticity and we measure the kinetics of this plasticity
at the single cell level. Importantly, standard of care chemotherapies in this disease preferentially kill specific
cancer cell states. In this proposal, we posit that understanding the facets of SCLC's intratumoral heterogeneity
will: 1) contribute to our understanding of a poorly characterized aspect of cancer heterogeneity; 2) reveal how
stochasticity and/or ecological cues in single-cell behaviors promote phenotypic equilibrium 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 translational methods pertinent
to this proposal including human-derived in vivo and ex vivo model systems, single-cell RNA sequencing, bulk
genetic and expression analysis, single cell fluorescence tracking, and mathematical and statistical modeling.
Our integrative approach is poised to formulate and validate a unified model of cellular states and 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 epigenetic reprogramming (SA3)
will advance a unique scientific canvas for the study of this highly lethal disease.

Grant Number: 4U01CA268052-04
NIH Institute/Center: NIH
Principal Investigator: Mohamed Abazeed