TMIC-34. Targeting mechanically regulated cell state in glioblastoma

Abstract Glioblastoma (GBM) is a highly invasive brain tumour. During invasion, tumour cells encounter mechanical microenvironments with varying tissue stiffness. How tissue mechanics regulate GBM cell state to influence tumour progression is poorly understood. We found that GBM cells display two predominant morphological states: mesenchymal and amoeboid states. GBM-brain interface and axon-rich regions harbor a greater proportion of tumour cells with the mesenchymal state compared to tumour core and axon-poor regions. We identified that TACAN, a putative fatty acid elongase, is a regulator of mesenchymal versus amoeboid cell state in GBM. Stiff substrate promotes the mesenchymal cell state in a TACAN-dependent manner. Mechanistically, TACAN regulates cholesterol and sphingolipids, the structural constituents of lipid raft. TACAN knockdown disrupts lipid raft-organized focal adhesion kinase signaling, neuron-GBM contact, and neuron-induced GBM cell proliferation. In orthotopic xenograft mouse models, TACAN knockdown mitigates GBM growth and prolongs mouse survival. Together, our results establish TACAN as a substrate stiffness reader, which promotes mesenchymal cell state-enriched lipid raft to govern tumour cell-intrinsic focal adhesion kinase signaling and tumour cell-neuron communication, which collectively enhance GBM growth. Targeting TACAN is a strategy to disrupt tissue mechanics-regulated cell state to treat GBM.