Spatially resolved gene expression and tumour-microenvironment interactions across malignant transformation in IDH-mutant glioma
- 1The Arthur and Sonia Labatt Brain Tumour Research Center, The Hospital for Sick Children
Abstract
Isocitrate dehydrogenase (IDH)-mutant gliomas represent most lower-grade diffuse gliomas in young adults. Although IDH-mutant gliomas initially behave indolently relative to IDH-wildtype counterparts, they undergo inevitable malignant transformation. The mechanisms driving this progression remain poorly defined. We analyzed a unique longitudinal cohort of two patients with IDH-mutant diffuse gliomas, each with matched WHO grade 2, 3, and 4 tumours. Spatial transcriptomics (NanoString GeoMx and 10X Visium), combined with differential expression, spatially variable gene analysis, and gene ontology enrichment, were used to define transcriptional programs underlying progression. Unexpectedly, across both patients, higher-grade tumours demonstrated reduced proliferation at the infiltrative margin as measured by Ki67. Spatial transcriptomic analysis identified an enrichment of invasion-associated genes associated with increasing tumour grade. In an independent bulk RNA-seq cohort, expression of this spatially derived program did not outperform grade-only PFS or OS analysis. These observations underscore the need to develop new metrics that account for spatial evolution that occurs across progression, but escapes detection in bulk analyses and provide the rationale for prioritizing migration-, cytoskeletal- and stress-associated programs for further investigation.
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BibTeX
@misc{ivanova2026spatially,
title = {{Spatially resolved gene expression and tumour-microenvironment interactions across malignant transformation in IDH-mutant glioma}},
author = {A. Ivanova and S. Ayyadhury and D. G. Munoz and M. Hopkins and F. Aboualizadeh and M. Spears and M. Wu and T. Pugh and R. G. W. Verhaak and D. P. Cahill and S. Das},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.08.749421},
url = {https://www.biorxiv.org/content/10.64898/2026.09.08.749421v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Spatially resolved gene expression and tumour-microenvironment interactions across malignant transformation in IDH-mutant glioma
AU - A. Ivanova
AU - S. Ayyadhury
AU - D. G. Munoz
AU - M. Hopkins
AU - F. Aboualizadeh
AU - M. Spears
AU - M. Wu
AU - T. Pugh
AU - R. G. W. Verhaak
AU - D. P. Cahill
AU - S. Das
PY - 2026
DA - 2026/09/08
PB - bioRxiv
DO - 10.64898/2026.09.08.749421
UR - https://www.biorxiv.org/content/10.64898/2026.09.08.749421v1
AB - Isocitrate dehydrogenase (IDH)-mutant gliomas represent most lower-grade diffuse gliomas in young adults. Although IDH-mutant gliomas initially behave indolently relative to IDH-wildtype counterparts, they undergo inevitable malignant transformation. The mechanisms driving this progression remain poorly defined. We analyzed a unique longitudinal cohort of two patients with IDH-mutant diffuse gliomas, each with matched WHO grade 2, 3, and 4 tumours. Spatial transcriptomics (NanoString GeoMx and 10X Visium), combined with differential expression, spatially variable gene analysis, and gene ontology enrichment, were used to define transcriptional programs underlying progression. Unexpectedly, across both patients, higher-grade tumours demonstrated reduced proliferation at the infiltrative margin as measured by Ki67. Spatial transcriptomic analysis identified an enrichment of invasion-associated genes associated with increasing tumour grade. In an independent bulk RNA-seq cohort, expression of this spatially derived program did not outperform grade-only PFS or OS analysis. These observations underscore the need to develop new metrics that account for spatial evolution that occurs across progression, but escapes detection in bulk analyses and provide the rationale for prioritizing migration-, cytoskeletal- and stress-associated programs for further investigation.
ER -