Activation of PPAR? in Myeloid Cells Promotes Progression of Epithelial Lung Tumors through TGF?1.

ABSTRACT: 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 PPAR? 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? activation in myeloid cells promotes the production of TGF?1, which, in turn, acts on CMT167 cancer cells to increase migration and induce an epithelial-mesenchymal transition (EMT). Targeting TGF?1 signaling in CMT167 cells prevented their growth and metastasis in vivo. Similarly, another mouse lung adenocarcinoma cell line with a Kras mutation, LLC, induced TGF?1 in myeloid cells through PPAR? activation. However, LLC cells are more mesenchymal and did not undergo EMT in response to TGF?1, nor did LLC require TGF?1 signaling for metastasis in vivo. Converting CMT167 cells to a mesenchymal phenotype through overexpression of ZEB1 made them unresponsive to TGF?1 receptor inhibition. The ability of TGF?1 to induce EMT in lung tumors may represent a critical process in cancer progression. We propose that TGF? receptor inhibition could provide an additional treatment option for KRAS-mutant epithelial lung tumors.Implications: This study suggests that TGF? receptor inhibitors may be an effective therapy in a subset of KRAS-mutant patients with non-small cell lung cancer, which show an epithelial phenotype.

SUBMITTER: Sippel TR 

PROVIDER: S-EPMC7439607 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature