J Edward, van Veen, Michael, Scherzer, Julia, Boshuizen, Mollee, Chu, Annie, Liu, Allison, Landman, Shon, Green, Christy, Trejo, and Martin, McMahon
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., eLife digest Cancers appear when changes in the genetic information of a cell, also called mutations, allow it to multiply uncontrollably. The disease we know as “lung cancer” kills more people than any other cancer, but this term actually refers to different types of tumors that appear because of various mutations that happen in different kinds of lung cells. To complicate matters further, as lung cancer cells become more aggressive, they can stop appearing and behaving like the type of lung cell they came from. Yet, knowing the exact origin of the cancer is key, since it determines which treatment will work best to stop the disease in its tracks. Despite these differences, many lung cancer cells contain mutations that over-activate two molecular cascades called the MAP kinase and the PI3’-kinase pathways. Under normal conditions, these signaling pathways relay external messages to the inside of the cell, where they help cells multiply. Two separate mutations can respectively over-stimulate either the MAP kinase or the PI3’-kinase pathway, but it was unclear how these could work together to start and maintain aggressive lung tumors. Another unanswered question was how these cancer cells lose the characteristics of the healthy cells they came from. To address these issues, van Veen et al. genetically engineered mice that carry a mutation which activates the MAP kinase pathway. The lung cells with this genetic change also made a red fluorescent protein that marked cancer cells, so that these could be separated from the rest of the lung and analyzed. This revealed that cells with only the MAP kinase mutation turned into small and benign tumors that began in lung cells, known as “type 2” cells. The PI3’-kinase mutation alone could not even start a tumor. However, together the mutations made tumors much more aggressive. Cells that carried both mutations also stopped producing proteins normally made by type 2 cells, therefore causing the cells to lose their original identity. The mice created by van Veen et al. could help to understand how lung cancers develop in these animals and also in human lung cancer patients. Ultimately, this information could be used to design new cancer treatments, especially since both the MAP kinase and PI3’-kinase pathways contain many proteins that can be targeted with drugs.
