Main Projects
Project 1: Identifying gene regulatory programs that drive lung cancer progression
Genomic alterations that result in loss of the catalytic component of SWI/SNF complexes, SMARCA4, results in aggressive malignancy in vivo and is associated with poor patient outcomes in the clinic. We previously found that SMARCA4-deficient cancer cells have unique epigenetic states marked by the distinct activities of transcription factors – indicating unique trajectories and cell state transitions for these cells during tumor evolution. We aim to identify and understand the gene regulatory programs that play a functional role in driving aggressive malignancy in these cancers, using a combination of in vivo models, somatic gene editing, and chromatin profiling approaches. These studies may lead to new therapeutic targets or better treatment strategies for patients with lung cancers harboring SMARCA4 alterations.
Project 2: Modeling cancer-associated SWI/SNF variants in vitro and in vivo
Mutations in genes encoding for SWI/SNF subunits are prevalent in lung cancer, a subset of which are associated with poor patient survival. While many of these result in loss of the protein’s expression, others are point mutations that retain the mutant protein’s expression and may have hypomorphic or neomorphic functions. These heterogenous cancer-associated SWI/SNF variants may have overlapping or distinct effects on gene regulation, tumor biology and progression, and therapeutic responses. We are modeling precise cancer-associated SWI/SNF mutations to understand their downstream effects using precision genome editing techniques in lung cancer organoids and mice. These models allow us to gain a high-resolution understanding of SWI/SNF mutations in lung cancer and their consequences on the protein complex’s chromatin regulatory functions. These are also powerful preclinical tools to study tumor evolution, the tumor microenvironment, and therapeutic responses in vivo.
Project 3: Determining the biological basis for the cell-of-origin in lung adenocarcinoma
Defined genetic lesions lead to cancer in some cellular settings but not others; however, the underlying factors that dictate the ability of a cell to function as a tumor cell-of-origin are still poorly understood in many cancer types. Indeed, two distinct lung epithelial cell types that give rise to lung adenocarcinoma – alveolar type II cells and club cells – have differential sensitivities to malignant transformation upon Smarca4 loss. We are using chromatin profiling and genetic perturbation approaches in organoids and genetically engineered mouse models to determine the factors that contribute to the ability of these two cell types to be transformed in the setting of Smarca4 inactivation. These studies may lead to the identification of factors we can perturb to render cells refractory to malignant transformation. Broadly, these will have implications for the tissue-specific patterns of SWI/SNF subunit mutations observed across human cancer types.