| First Author | Sippel TR | Year | 2019 |
| Journal | Mol Cancer Res | Volume | 17 |
| Issue | 8 | Pages | 1748-1758 |
| PubMed ID | 31088909 | Mgi Jnum | J:277618 |
| Mgi Id | MGI:6342299 | Doi | 10.1158/1541-7786.MCR-19-0236 |
| Citation | Sippel TR, et al. (2019) Activation of PPARgamma in Myeloid Cells Promotes Progression of Epithelial Lung Tumors through TGFbeta1. Mol Cancer Res 17(8):1748-1758 |
| abstractText | 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 PPARgamma 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 PPARgamma activation in myeloid cells promotes the production of TGFbeta1, which, in turn, acts on CMT167 cancer cells to increase migration and induce an epithelial-mesenchymal transition (EMT). Targeting TGFbeta1 signaling in CMT167 cells prevented their growth and metastasis in vivo. Similarly, another mouse lung adenocarcinoma cell line with a Kras mutation, LLC, induced TGFbeta1 in myeloid cells through PPARgamma activation. However, LLC cells are more mesenchymal and did not undergo EMT in response to TGFbeta1, nor did LLC require TGFbeta1 signaling for metastasis in vivo. Converting CMT167 cells to a mesenchymal phenotype through overexpression of ZEB1 made them unresponsive to TGFbeta1 receptor inhibition. The ability of TGFbeta1 to induce EMT in lung tumors may represent a critical process in cancer progression. We propose that TGFbeta receptor inhibition could provide an additional treatment option for KRAS-mutant epithelial lung tumors.Implications: This study suggests that TGFbeta 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. |
