Spatial analysis reveals the evolving organization of low-grade and high-grade IDH-mutant glioma
Hoefflin, R.; Greenwald, A. C.; Galili Darnell, N.; Mount, C. W.; Tiomkin, Y.; Simkin, D.; Patterson, A. B.; Gonzalez Castro, L. N.; Goliand, I.; Golani, O.; Joseph, K.; Beck, J.; Ravi, V. M.; Kedmi, M.; Keren-Shaul, H.; Addadi, Y.; Neidert, M. C.; Suva, M. L.; Tirosh, I.
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Adult diffuse gliomas are comprised of malignant cell states interwoven with the non-malignant brain microenvironment. Here we combine spatial transcriptomics and spatial proteomics of IDH-mutant gliomas to define organizational principles across histological grades. In low-grade tumors, spatial organization arises from underlying nonmalignant brain structures. For example, we classify low-grade tumor regions as embedded into white matter and identify a sharp white-grey matter junction that restricts cortical invasion and is associated with marked changes in tumor composition and cellular phenotypes. This junction is preferentially traversed by oligodendrocyte progenitor (OPC)-like malignant cells, which may drive tumor expansion. In contrast, intermediate-grade tumors are largely disorganized, with few recurring pairwise interactions between cancer cell states and TME cell types. In high-grade tumors, hypoxia/necrosis-associated global structure begins to emerge, reminiscent of IDH-wildtype glioblastoma. Together, these findings reveal two independent axes of glioma spatial organization--from brain anatomy-driven organization in low-grade tumors to hypoxia-associated structure in high-grade tumors--and establishes a framework that links tumor grade to recurrent spatial associations between cell states and cell types.
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