Abstract:
: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.
journal_name
Elifejournal_title
eLifeauthors
van Veen JE,Scherzer M,Boshuizen J,Chu M,Liu A,Landman A,Green S,Trejo C,McMahon Mdoi
10.7554/eLife.43668subject
Has Abstractpub_date
2019-08-27 00:00:00issn
2050-084Xpii
43668journal_volume
8pub_type
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