Transcriptional Regulation of Lung Cancer Identity

Project Summary Lung adenocarcinoma, the most common cause of cancer death worldwide, exhibits substantial heterogeneity in cellular identity, or differentiation state. In this disease, cancer cell identity correlates with critical clinical parameters, including patient prognosis, intrinsic sensitivity to therapy, and acquisition of drug resistance. Thus, there is an unmet need to obtain a comprehensive understanding of mechanisms controlling LUAD identity. A major rationale for this proposal is that a mechanistic understanding of the complex interplay between lineage specifiers and oncogenic signaling pathways in LUAD must be achieved before such therapeutic strategies can be developed. The immediate goal of this application is to test the central hypothesis that lineage specifiers and oncogenic signaling pathways coordinately modulate LUAD identity and growth. This hypothesis will be tested in the following specific aims via an integrative experimental approach employing genetically engineered mouse models (GEMMs), organoid cultures, human PDX models/cell lines and clinically relevant pathway inhibitors: (1) Identify mechanisms by which FoxA1/2 promote tumorigenesis and activate a mixed-lineage state in NKX2-1-positive lung adenocarcinoma. (2) Identify mechanisms by which oncogenic signaling pathways regulate identity in NKX2-1-negative lung adenocarcinoma.