Sunday, May 11, 2025
5/11/2025
Epigenetic regulation of NKX2-1-negative lung adenocarcinoma cellular identity by FoxA1 and FoxA2 - PROJECT ABSTRACT Lung cancer is the leading cause of cancer mortality in both men and women. Despite advances in screening methods and personalized therapy, patient prognosis remains dismal with 5-year survival rates varying from 4- 17%. Lung adenocarcinoma (LUAD), the most frequently diagnosed subtype of this disease, exhibits substantial heterogeneity in its cellular identity or tissue differentiation state. Changes in cellular identity have been shown to strongly correlate with clinical parameters including patient prognosis, sensitivity to chemotherapy, and development of drug resistance. Currently, the field lacks a comprehensive understanding of the molecular networks that regulate lung adenocarcinoma cell identity and govern tumor progression. Identifying master transcriptional regulators will provide novel insight into the mechanisms of cancer progression and lay the groundwork for the development of therapeutic strategies specific to tumor differentiation state. Invasive mucinous adenocarcinoma (IMA) is a subtype of LUAD that undergoes pulmonary to gastric lineage switching during its natural progression. Using genetically engineered mouse models, we have found that loss of the pulmonary lineage specifier NKX2-1/TTF1 causes gastric transdifferentiation in LUAD, generating murine tumors that recapitulate the morphology and gene expression profile of human IMA. This gastric lineage switch is mediated in part by differential chromatin binding of pioneer factors, FoxA1 and FoxA2 (FoxA1/2), which relocate throughout the genome from pulmonary loci to regulatory elements of gastric genes. Upon NKX2-1 loss, these gastric genes also undergo chromatin modifications associated with gene activation including increases in histone 3 lysine 27 acetylation (H3K27ac). However, it is unknown whether FoxA1/2 are required to mediate these chromatin alterations at their de novo binding sites and thereby, facilitate tumor lineage switching. In addition to regulating the pulmonary-to-gastric transdifferentiation, FoxA1/2 also modulate LUAD identity in response to targeted therapy. Pharmacologic inhibition of the mitogen-activated protein kinase signaling cascade not only causes tumor regression in NKX2-1-negative LUAD, but also results in a gastric lineage switch that is dependent upon FoxA1/2 activity. Thus, the objective of this proposal is to determine the mechanism by which FoxA1/2 modulate the chromatin landscape of NKX2-1-negative LUAD in order to control cancer identity. The central hypothesis is that FoxA1/2 restructure chromatin accessibility and modify the histone/ DNA methylation landscape in order to control LUAD identity. To test this hypothesis, we will determine whether FoxA1/2 are required for chromatin modulation following Nkx2-1 deletion in established tumors and define the precise mechanism by which FoxA1/2 mediate these changes. This proposal is significant because it will provide a deeper understanding of the molecular networks that regulate LUAD cellular identity and tumor progression, findings which are essential for the development of subtype-specific interventions.
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