Mutationally-activated PI3’-kinase-α promotes de-differentiation of lung tumors initiated by the BRAFV600E oncoprotein kinase
| Autor: | Michael T. Scherzer, Shon Green, Allison Landman, Annie Liu, Christy L. Trejo, J. Edward van Veen, Martin McMahon, Mollee Chu, Julia Boshuizen |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
QH301-705.5 Science Cell Biology PI3K General Biochemistry Genetics and Molecular Biology BRAF 03 medical and health sciences 0302 clinical medicine medicine Biology (General) Lung cancer Transcription factor PI3K/AKT/mTOR pathway General Immunology and Microbiology de-differentiation Kinase PGC1a General Neuroscience General Medicine Lipid signaling respiratory system lung adenocarcinoma medicine.disease 3. Good health 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research Medicine Adenocarcinoma FOXA1 |
| Zdroj: | eLife, Vol 8 (2019) |
| ISSN: | 2050-084X |
| DOI: | 10.7554/elife.43668 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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