Activation of PPARγ in Myeloid Cells Promotes Progression of Epithelial Lung Tumors through TGFβ1.

Lung cancer is a heterogeneous disease in which patient-specific treatments are desirable and the development of targeted therapies has been effective. Although mutations in are frequent in lung adenocarcinoma, there are currently no targeted agents against KRAS. Using a mouse lung adenocarcinoma cell line with a mutation (CMT167), we previously showed that PPARγ activation in lung cancer cells inhibits cell growth yet promotes tumor progression when activated in myeloid cells of the tumor microenvironment. Here, we report that PPARγ activation in myeloid cells promotes the production of TGFβ1, which, in turn, acts on CMT167 cancer cells to increase migration and induce an epithelial-mesenchymal transition (EMT). Targeting TGFβ1 signaling in CMT167 cells prevented their growth and metastasis . Similarly, another mouse lung adenocarcinoma cell line with a mutation, LLC, induced TGFβ1 in myeloid cells through PPARγ activation. However, LLC cells are more mesenchymal and did not undergo EMT in response to TGFβ1, nor did LLC require TGFβ1 signaling for metastasis . Converting CMT167 cells to a mesenchymal phenotype through overexpression of ZEB1 made them unresponsive to TGFβ1 receptor inhibition. The ability of TGFβ1 to induce EMT in lung tumors may represent a critical process in cancer progression. We propose that TGFβ receptor inhibition could provide an additional treatment option for -mutant epithelial lung tumors. This study suggests that TGFβ receptor inhibitors may be an effective therapy in a subset of -mutant patients with non-small cell lung cancer, which show an epithelial phenotype.