Single-nucleus and spatial landscape of the sub-ventricular zone in human glioblastoma

Licon-Munoz, Y.; Avalos, V.; Subramanian, S.; Granger, B.; Martinez, F.; Varela, S.; Moore, D.; Perkins, E.; Kogan, M.; Berto, S.; Chohan, M. O.; Bowers, C. A.; Piccirillo, S. G. M.

doi:10.1101/2024.04.24.590852

bioRxiv · 10.1101/2024.04.24.590852

Single-nucleus and spatial landscape of the sub-ventricular zone in human glioblastoma

Licon-Munoz, Y.·Avalos, V.·Subramanian, S.·Granger, B.·Martinez, F.·Varela, S.·Moore, D.·Perkins, E.·Kogan, M.·Berto, S.·Chohan, M. O.·Bowers, C. A.·Piccirillo, S. G. M.

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Abstract

The sub-ventricular zone (SVZ) is the most well-characterized neurogenic area in the mammalian brain. We previously showed that in 65% of patients with glioblastoma (GBM), the SVZ is a reservoir of cancer stem-like cells that contribute to treatment resistance and emergence of recurrence. Here, we built a single-nucleus RNA-sequencing-based microenvironment landscape of the tumor mass (T_Mass) and the SVZ (T_SVZ) of 15 GBM patients and 2 histologically normal SVZ (N_SVZ) samples as controls. We identified a mesenchymal signature in the T_SVZ of GBM patients: tumor cells from the T_SVZ relied on the ZEB1 regulatory network, whereas tumor cells in the T_Mass relied on the TEAD1 regulatory network. Moreover, the T_SVZ microenvironment was predominantly characterized by tumor-supportive microglia, which spatially co-exist and establish heterotypic interactions with tumor cells. Lastly, differential gene expression analyses, predictions of ligand-receptor and incoming/outgoing interactions, and functional assays revealed that the IL-1{beta}/IL-1RAcP and Wnt-5a/Frizzled-3 pathways are therapeutic targets in the T_SVZ microenvironment. Our data provide insights into the biology of the SVZ in GBM patients and identify specific targets of this microenvironment.

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Licon-Munoz, Y., Avalos, V., Subramanian, S., Granger, B., Martinez, F., Varela, S., Moore, D., Perkins, E., Kogan, M., Berto, S., Chohan, M. O., Bowers, C. A., Piccirillo, S. G. M.. 2024-04-27. Single-nucleus and spatial landscape of the sub-ventricular zone in human glioblastoma. https://doi.org/10.1101/2024.04.24.590852

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