MARCKS as a Target for Pathological Tunneling Nanotubes in Glioblastoma

During glioblastoma (GBM) progression, therapeutic resistance is influenced by a heterogeneous network of tumor- and tumor-promoting cells in the tumor microenvironment. Biological attacks against tumor cells (i.e. chemoradiotherapy) induce tumoral defense mechanisms bolstered by sophisticated communication mechanisms and aberrant signaling pathways. Tunneling nanotubes (TNTs) have been well documented to mediate this process by aiding the metabolic rescue of tumor cells or facilitating the recruitment and reprogramming of normal cells to become tumor-supportive. GBM brain tumor-initiating cells (BTIC) target normal human astrocytes (NHA) using TNTs, therefore investigating this interaction and the potential mediators involved is critical. Myristoylated Alanine Rich C-Kinase Substrate (MARCKS) has never been investigated as a potential regulator of TNTs despite several overlapping signaling pathways. In the present study, we demonstrate a role for the MARCKS effector domain (ED) and PKC activation in the formation and functionality of TNTs between GBM BTICs and NHAs. We employ a cell-penetrable peptide derived from MARCKS effector domain (MED2), PKC-targeting drugs, and an inducible MARCKS ED U87 model to elucidate a potential role for MARCKS and PKC in TNT regulation between GBM cells and NHAs.