Huntsman Cancer Institute, University of Utah, Salt Lake City, United States; Department of Dermatology, University of Utah, Salt Lake City, United States; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States; Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
Michael Scherzer
Huntsman Cancer Institute, University of Utah, Salt Lake City, United States; Department of Dermatology, University of Utah, Salt Lake City, United States
Julia Boshuizen
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States; Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
Mollee Chu
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States; Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
Annie Liu
Huntsman Cancer Institute, University of Utah, Salt Lake City, United States; Department of Dermatology, University of Utah, Salt Lake City, United States
Allison Landman
Huntsman Cancer Institute, University of Utah, Salt Lake City, United States; Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
Shon Green
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States; Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
Christy Trejo
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States; Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
Huntsman Cancer Institute, University of Utah, Salt Lake City, United States; Department of Dermatology, University of Utah, Salt Lake City, United States; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States; Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
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 BRAFV600E 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 BRAFV600E-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 BrafCAT allele in which CRE-mediated recombination leads to co-expression of BRAFV600E and tdTomato. We demonstrate that co-expression of BRAFV600E and PIK3CAH1047R 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.
