Spatial multi-omics defines a shared infiltrative signature in glioblastoma at the resection margin

Pai, B.; Ramos, S. I.; Cheng, W. S.; Joshi, T.; Price, G.; Tome-Garcia, J.; Nudelman, G.; Shroff, S.; Beaumont, K.; Raymund, Y.; Sebra, R.; Zaslavsky, E.; Tsankova, N. M.

doi:10.1101/2024.11.05.621879

bioRxiv · 10.1101/2024.11.05.621879

Spatial multi-omics defines a shared infiltrative signature in glioblastoma at the resection margin

Pai, B.·Ramos, S. I.·Cheng, W. S.·Joshi, T.·Price, G.·Tome-Garcia, J.·Nudelman, G.·Shroff, S.·Beaumont, K.·Raymund, Y.·Sebra, R.·Zaslavsky, E.·Tsankova, N. M.

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Abstract

Glioblastoma (GBM) remains an untreatable disease. Understanding GBMs infiltrative biology at the resection margin is limited, despite causing disease recurrence and progression. To address this, we generated a high-throughput single-nucleus (sn)RNA-seq and snATAC-seq multi-omic dataset from six tumors with distinct genomic drivers and combined it with spatial transcriptomics to characterize the unique molecular phenotype of GBM near the margin. By contrasting GBM-specific biology in matching "Core" vs. "Margin" dissections, we define unique, shared "GBM infiltration" and chromatin accessibility signatures near the margin. We prioritize EGFR as a top differentially expressed and accessible "Margin" marker across GBM subtypes, show its dynamic expression along a core-to-margin infiltration trajectory, and validate its role in migration through CRISPR/Cas9 deletion in two patient-derived models. ChIP-seq studies furthermore corroborate preferential TEAD1 binding at EGFRs accessible regulatory elements. This validated multi-omic dataset enables further studies into tumor and microenvironment biology in the context of residual GBM disease.

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Pai, B., Ramos, S. I., Cheng, W. S., Joshi, T., Price, G., Tome-Garcia, J., Nudelman, G., Shroff, S., Beaumont, K., Raymund, Y., Sebra, R., Zaslavsky, E., Tsankova, N. M.. 2024-11-08. Spatial multi-omics defines a shared infiltrative signature in glioblastoma at the resection margin. https://doi.org/10.1101/2024.11.05.621879

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