ANGI-12. TGF-Β PROMOTES THE INVASION OF GLIOBLASTOMA THROUGH UPREGULATION OF COL6A1

Abstract Glioblastoma (GBM) is an aggressive primary brain tumor characterized by its highly invasion nature, which contributes to poor prognosis. A better understanding of the molecular mechanisms underlying GBM invasion is essential for developing novel targeted therapies. Transforming growth factor beta (TGF-β) is known to induce the transition of GBM from a proneural to a more invasive mesenchymal subtype. However, the downstream target genes that primarily drives TGF-β mediated invasion remains poorly defined. Here we hypothesize that the COL6A1 induced by TGF-β serves as a key mediator of TGF-β drive invasion in GBM. In this study, we used RNA sequencing to identify genes upregulated in response to TGF- β treatment in GBM cells. Differential expression analysis revealed a strong enrichment of genes involved in extracellular matrix (ECM) organization, with COL6A1 emerging as one of the most significantly upregulated genes. Moreover, elevated expression of COL6A1 is highly associated with poor prognosis of GBM patients. Matrigel transwell and spheroid invasion assays demonstrated that siRNA-mediated knockdown of COL6A1 markedly inhibited TGF-β induced invasion. Moreover, immunohistochemical analysis of human GBM specimens showed a strong positive correlation between COL6A1 expression and phosphorylated SMAD2, a key effector of canonical TGF-β signaling. These findings support our hypothesis that TGF-β drives GBM invasion through upregulation of COL6A1, which likely facilitates cell-ECM interactions via integrin-binding motifs such as RGD. We will further validate the in vitro findings using preclinical mouse models. In summary, our data identify COL6A1 as a critical downstream effector of TGF-β mediated invasion in GBM and highlight its potential as a novel therapeutic target to inhibit tumor invasion and improve patient outcomes.