Network Control of Cell Identity and Plasticity in Small Cell Lung Cancer
Groves, Sarah Maddox
Dissertation under the direction of Dr. Vito Quaranta Epigenetic heterogeneity underlies acquired resistance to therapy in several cancer types. Small cell lung cancer (SCLC) is a particularly recalcitrant form of lung cancer that metastasizes early and quickly develops resistance to the standard of care in most patients. This work aims to understand the phenotypic heterogeneity and plasticity of SCLC using top-down and bottom-up modeling approaches to identify strategies for overcoming resistance. A novel inference tool, BooleaBayes, identified a gene regulatory network controlling SCLC cell identity. BooleaBayes simulations and in silico perturbations suggested methods for reprogramming SCLC cells to a drug-sensitive state. This pipeline was applied to a variant MYC-driven mouse model of SCLC with ASCL1 loss and identified key regulators of phenotype transitions in this model. Archetype analysis was used to determine how SCLC cells trade-off performance of PNEC-related tasks for increased tumor survival. Plasticity was then quantified using an RNA velocity-based Markov model and showed SCLC cells can trade-off between these tasks by regulating their Transport Potential. Identifying regulators of plasticity in SCLC suggested targets for increasing the stability of cell identity to overcome the evasion of therapy seen in patients. The plasticity pipeline, applied to xenograft models before and after treatment, showed that a highly-plastic, non-NE subpopulation of the relapsed tumors could regenerate the now-resistant NE compartment of the tumor. Together, this work increases our understanding of how the phenotype is regulated and suggests treatment strategies that target plasticity to overcome acquired resistance.