Transmembrane protein VMP1 dysregulation in modulating tumor growth and angiogenesis in glioblastoma

Abstract

Glioblastoma (GBM) represents the most malignant type of primary tumors in the central nervous system of adults. Existing treatment modalities for GBM include surgical removal, radiotherapy, chemotherapy, immunotherapy, tumor treating fields or a combination of the above. Although great advances have been achieved over the past decades, prognosis of GBM patients remains largely unchanged with a median survival time of less than 2 years. The inability to cure this disease largely lies in the rapid proliferation, migration/invasion, high heterogeneity, and treatment resistance. Therefore, a better understanding of the pathogenesis of GBM is urgently needed for the development of more effective treatment strategies.

Transmembrane proteins (TMEMs) are a type of proteins that reside in and cross the biological membranes for one or multiple times and crucial in multiple biological processes. Vacuole membrane protein 1 (VMP1) is one member of the TMEM family and dysregulation of VMP1 have been implicated in various cancers. However, the roles of VMP1 in cancer is controversial and its role in the pathogenesis of glioblastoma remains undefined.

In the present study, this candidate firstly determined the upregulation of VMP1 in glioblastoma compared to normal brain tissues using publicly available datasets (GEPIA, CGGA, and R2) and the candidate’s cohort of clinical specimens. Moreover, Kaplan Meier survival and Cox proportional hazard regression analyses revealed that high VMP1expression is associated with worse overall survival of glioma patients but may not serve as an independent diagnostic biomarker for GBM patients.

Functional characterization of VMP1 was then performed with loss- and gain-of-function studies and found that VMP1 exerted oncogenic effects on GBM growth in vivo but not in vitro. The inconsistency between in vitro and in vivo findings suggested that VMP1-mediated oncogenic effects might be dependent on a three-dimensional microenvironment. Bioinformatic analysis predicted that VMP1 dysregulation could be associated with altered extracellular matrix (ECM)-receptor interaction and angiogenesis in GBM. Concertedly, direct forced expression of VMP1 was associated with significant increases in the diameter of GBM spheroids in ECM-coated cell culture and the number and diameter of blood vessels in both subcutaneous and intracranial xenografts. Moreover, VMP1-overexpressing cells-derived soluble pro-angiogenic factors were found to activate the angiogenic switch in endothelial cells in both ECM-dependent and -independent manners possibly via β-catenin and LOX-mediated signaling pathways, which in turn conferred growth advantage in GBM cells.

This study for the first time provides preclinical evidence on the putative oncogenic roles of VMP1 in modulating tumor growth and angiogenesis in GBM. The functional discrepancies of VMP1 between two-dimensional in vitro cell culture and in vivo animal model may partially explain the controversial findings in other malignancies. It also provides novel insights into therapeutic potential of targeting VMP1 for the treatment of GBM in the future.