Discovery of an evolutionarily conserved GPCR-like protein shaping glioblastoma cell networks

Glioblastoma multiforme (GBM) is among the most aggressive and lethal brain cancers, and despite advances in surgery, radiation, and chemotherapy, median survival remains approximately 20 months. A defining morphological feature of GBM is the formation of tumor microtubules (TMs), thin cytoplasmic extensions that create open-ended channels between tumor cells. These structures transform isolated GBM cells into a coordinated multicellular network capable of rapidly transferring cytoplasmic components across distance, reshaping tumor behavior and promoting therapy resistance. Using AI-driven structural approaches, our lab identified TM184C, an ancient GPCR-like protein that regulates autophagy and the formation of intercellular connections and transcellular material and organelle transfer. Notably, HEK293A cells overexpressing TM184C generate intercellular connections that phenocopy the TM184C-positive structures and vesicle distributions observed in patient-derived GBM cells. Given these findings, and the observation that TM184C expression correlates with poor prognosis in GBM, we will report on our efforts to define how TM184C contributes to GBM projections, intercellular connectivity, and tumor progression.