Activation of PPARγ in Myeloid Cells Promotes Progression of Epithelial Lung Tumors Through TGF-β1.

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 KRAS are frequent in lung adenocarcinoma, there are currently no targeted agents against KRAS. Using a mouse lung adenocarcinoma cell line with a Kras mutation (CMT167), we previously showed that PPARg activation in lung cancer cells inhibits cell growth in vitro yet promotes tumor progression when activated in myeloid cells of the tumor microenvironment. Here, we report that PPAR gamma activation in myeloid cells promotes the production of TGF beta 1, which, in turn, acts on CMT167 cancer cells to increase migration and induce an epithelial-mesenchymal transition (EMT). Targeting TGF beta 1 signaling in CMT167 cells prevented their growth andmetastasis in vivo. Similarly, anothermouse lung adenocarcinoma cell line with a Kras mutation, LLC, induced TGF beta 1 in myeloid cells through PPAR gamma activation. However, LLC cells are more mesenchymal and did not undergo EMT in response to TGF beta 1, nor did LLC require TGF beta 1 signaling for metastasis in vivo. Converting CMT167 cells to a mesenchymal phenotype through overexpression of ZEB1 made them unresponsive to TGF beta 1 receptor inhibition. The ability of TGF beta 1 to induce EMT in lung tumors may represent a critical process in cancer progression. We propose that TGF beta receptor inhibition could provide an additional treatment option for KRAS-mutant epithelial lung tumors.