Mutationally-activated PI3’-kinase-α promotes de-differentiation of lung tumors initiated by the BRAF(V600E) oncoprotein kinase

Human lung adenocarcinoma exhibits a propensity for de-differentiation, complicating diagnosis and treatment, and predicting poorer patient survival. In genetically engineered mouse models of lung cancer, expression of the BRAF(V600E) oncoprotein kinase initiates the growth of benign tumors retaining characteristics of their cell of origin, AT2 pneumocytes. Cooperating alterations that activate PI3’-lipid signaling promote progression of BRAF(V600E)-driven benign tumors to malignant adenocarcinoma. However, the mechanism(s) by which this cooperation occurs remains unclear. To address this, we generated mice carrying a conditional Braf(CAT) allele in which CRE-mediated recombination leads to co-expression of BRAF(V600E) and tdTomato. We demonstrate that co-expression of BRAF(V600E) and PIK3CA(H1047R) in AT2 pneumocytes leads to rapid cell de-differentiation, without decreased expression of the transcription factors NKX2-1, FOXA1, or FOXA2. Instead, we propose a novel role for PGC1α in maintaining AT2 pneumocyte identity. These findings provide insight into how these pathways may cooperate in the pathogenesis of human lung adenocarcinoma.