Multivalent state transitions regulate the intratumoral composition of small cell lung carcinoma.

• DOI: 10.1200/jco.2021.39.15_suppl.e20587
• Publication Date: 2021-06-02T14:56:33Z
• Authors: Priyanka Gopal; Aaron Petty; Rohan Bareja; Titas Bera; Kevin Rogacki; Jyoti D. Patel; Craig Peacock; Mohamed E. Abazeed
• Keywords: Ex vivo; YAP1

e20587 Background: Small cell lung carcinoma (SCLC) is an aggressive, tobacco-associated tumor with neuroendocrine features characterized by rapid growth, metastatic progression, and initial response followed almost invariable resistance to therapy. Studies date have not resolved the extent that diverse transcriptional programs drive SCLC contribute its lethality. Methods: We combined one of largest most inventories patient-derived xenograft models ex vivo culture system maintains fidelity matched primary identify state heterogeneity. Using expression Ascl1, NeuroD1, Yap1 as markers well-conserved states, we developed a state-of-the-art fluorescent platform can directly measure single-cell transitions in multi-layered ecosystem using tandemly integrated reporters. modeled population dynamics discrete time Markov chain transitions. Results: show significant cell-state heterogeneity several tumors, xenografts (PDX), cultures. These states comprise distinct subpopulations marked master regulatory transcription factors (TFs) Yap1. Ex vivo, 3 TFs are associated suspension aggregates small cells, pre-suspension (loosely adherent) aggregates, large mesenchymal cells visible cytoplasm spindle-like membrane extensions, respectively. observed equilibria proportions tumors both (PDX) vivo. In addition, shown “elasticity” responses, measured clinical during chemotherapy relapse from end therapy, dependent on TF levels. observations suggest mechanistic modeling intra-tumoral high relevance. Conclusions: Our integrative approach poised formulate validate unified model cellular program diversity SCLC. If successful, characterization malignant ontogenic programs, their plasticity, advancement new therapies designed combat plasticity epigenetic reprogramming will create scientific canvas for study this highly lethal disease.