BMP7 is a growth factor playing pro- or anti-oncogenic roles in cancer in a cell type-dependent manner. We previously reported that the BMP7 gene is overexpressed in pheochromocytomas (PCCs) developing in MENX-affected rats and human patients. Here, analyzing a large cohort of PCC patients, we found that 72% of cases showed elevated levels of the BMP7 protein. To elucidate the role of BMP7 in PCC, we modulated its levels in PCC cell lines (overexpression in PC12, knockdown in MPC and MTT cells) and conducted functional assays. Active BMP signaling promoted cell proliferation, migration, and invasion, and sustained survival of MENX rat primary PCC cells. In PCC, BMP7 signals through the PI3K/AKT/mTOR pathway and causes integrin ß1 upregulation. Silencing integrin ß1 in PC12 cells suppressed BMP7-mediated oncogenic features. Treatment of MTT cells with DMH1, a novel BMP antagonist, suppressed proliferation and migration. To verify the clinical applicability of our findings, we evaluated a dual PI3K/mTOR inhibitor (NVP-BEZ235) in MENX-affected rats in vivo. PCCs treated with NVP-BEZ235 had decreased proliferation and integrin ß1 levels, and higher apoptosis. Altogether, BMP7 activates pro-oncogenic pathways in PCC. Downstream effectors of BMP7-mediated signaling may represent novel targets for treating progressive/inoperable PCC, still orphan of effective therapy.

Bone morphogenic protein 7, Integrin beta 1, MENX rats, Pheochromocytoma, PI3K pathway,
This work was funded by the European Commission 7th Framework Programme; grant id fp7/259735 - European Network for the Study of Adrenal Tumours - Structuring clinical research on adrenal cancers in adults (ENS@T-CANCER)
Department of Pathology

Leinhäuser, I, Richter, A, Lee, M, Höfig, I, Anastasov, N, Fend, F, … Pellegata, N. (2015). Oncogenic features of the bone morphogenic protein 7 (BMP7) in pheochromocytoma. Oncotarget, 6(36), 39111–39126. doi:10.18632/oncotarget.4912