TGF-β induces oncofetal fibronectin, which in turn modulates TGF-β superfamily signaling in endothelial cells

Abstract

Gene splicing profiles are frequently altered in cancer, and the splice variants of fibronectin (FN) containing the extra-domains A (EDA) and B (EDB) referred to as EDA+FN and EDB+FN are highly up-regulated in tumor vasculature. TGF-β signaling has been attributed a pivotal role in glioblastoma, with TGF-β promoting angiogenesis and vessel remodeling. By immunohistochemical staining, we observed that the oncofetal FN isoforms EDA+FN and EDB+FN are expressed in glioblastoma vasculature. Ex vivo single cell gene expression profiling of patients’ tumors using the markers CD31 and alpha-smooth muscle actin (αSMA) respectively confirmed the predominant expression of FN, EDA+FN, and EDB+FN in the vascular compartment of glioblastoma. Specifically, within the CD31-positive cell population, we identified a trend of positive correlation in the expression of EDA+FN and EDB+FN with molecules associated with TGF-β signaling. Further, TGF-β induced EDA+FN and EDB+FN in human cerebral microvascular endothelial cells and glioblastoma-derived endothelial cells in a SMAD3/SMAD4-dependent manner. In turn, FN modulated TGF-β superfamily signaling in endothelial cells via the EDA and EDB domains, pointing towards a bidirectional influence between oncofetal FN and TGF-β superfamily signaling.