---
title: "Spatial transcriptomics reveals invasion-associated programs across malignant progression in IDH‑m"
id: "biorxiv-0-spatially-resolved-gene-expression-and-tumour-microenvironment-interactions"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-0-spatially-resolved-gene-expression-and-tumour-microenvironment-interactions"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.08.749421v1?rss=1"
published_at: "2026-09-16T09:15:58.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Spatial transcriptomics reveals invasion-associated programs across malignant progression in IDH‑m
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-0-spatially-resolved-gene-expression-and-tumour-microenvironment-interactions
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.08.749421v1?rss=1)
- **Published At:** 2026-09-16T09:15:58.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- This preprint analyses a unique longitudinal cohort of two patients with **IDH‑mutant** diffuse gliomas, each sampled at matched WHO grade 2, 3 and 4 timepoints to study malignant transformation. - The study applied spatial transcriptomics platforms (NanoString GeoMx and 10X Visium) and performed differential expression, spatially variable gene analysis, and gene ontology enrichment to define transcriptional programs associated with progression. - A key and unexpected observation was that higher‑grade tumours showed reduced proliferation at the infiltrative margin, as measured by **Ki67**, relative to lower‑grade samples from the same patients. - Spatial analysis identified an enrichment of **invasion‑associated genes** with increasing tumour grade; these programs emphasized migration-, cytoskeletal- and stress‑related biology. - When the spatially derived program was tested in an independent bulk RNA‑seq cohort, its expression did not outperform a grade‑only model for progression‑free survival (PFS) or overall survival (OS) prediction. - The findings highlight limitations of bulk RNA analyses to capture spatial evolution during malignant progression and argue for development of new spatially informed metrics and prioritization of migration, cytoskeletal and stress pathways for follow‑up investigations. - Data and code resources associated with the study are deposited in public repositories (GEO, BioProject, cBioPortal and GitHub) as reported by the authors. - The authors declare competing interests (financial relationships listed for specific authors) and acknowledge multiple funders; the manuscript is a preprint and not peer reviewed.
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Alyona Ivanova 1 The Arthur and Sonia Labatt Brain Tumour Research Center, The Hospital for Sick Children; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Alyona%2BIvanova%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Ivanova%20A&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AAlyona%2BIvanova%2B) * [ORCID record for Alyona Ivanova](http://orcid.org/0009-0003-7182-5528 "Open in new tab") * For correspondence: alyona.ivanova@mail.utoronto.ca Shamini Ayyadhury 2 Princess Margaret Cancer Centre, University Health Network; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Shamini%2BAyyadhury%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Ayyadhury%20S&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AShamini%2BAyyadhury%2B) * [ORCID record for Shamini Ayyadhury](http://orcid.org/0000-0002-8717-637X "Open in new tab") David G Munoz 3 Department of Laboratory Medicine, St. Michaels Hospital; 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* [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Farzaneh%2BAboualizadeh%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Aboualizadeh%20F&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AFarzaneh%2BAboualizadeh%2B) Melanie Spears 4 Ontario Institute for Cancer Research; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Melanie%2BSpears%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Spears%20M&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AMelanie%2BSpears%2B) * [ORCID record for Melanie Spears](http://orcid.org/0000-0002-1535-4675 "Open in new tab") Megan Wu 1 The Arthur and Sonia Labatt Brain Tumour Research Center, The Hospital for Sick Children; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Megan%2BWu%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Wu%20M&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AMegan%2BWu%2B) Trevor Pugh 2 Princess Margaret Cancer Centre, University Health Network; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Trevor%2BPugh%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Pugh%20T&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ATrevor%2BPugh%2B) Roel G W Verhaak 5 Yale University; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Roel%2BG%2BW%2BVerhaak%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Verhaak%20RG&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ARoel%2BG%2BW%2BVerhaak%2B) * [ORCID record for Roel G W Verhaak](http://orcid.org/0000-0003-2773-0436 "Open in new tab") Daniel P Cahill 6 Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Daniel%2BP%2BCahill%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Cahill%20DP&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ADaniel%2BP%2BCahill%2B) Sunit Das 7 Division of Neurosurgery, University of Toronto * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Sunit%2BDas%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Das%20S&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ASunit%2BDas%2B) * [ORCID record for Sunit Das](http://orcid.org/0000-0002-2146-4168 "Open in new tab") * [Abstract](https://www.biorxiv.org/content/10.64898/2026.09.08.749421v1)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_art/node:5782710/1) * [Info/History](https://www.biorxiv.org/content/10.64898/2026.09.08.749421v1.article-info)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_info/node:5782710/1) * [Metrics](https://www.biorxiv.org/content/10.64898/2026.09.08.749421v1.article-metrics)[](https://www.biorxiv.org/panels_ajax_tab/article_tab_metrics/node:5782710/1) * [Supplementary material](https://www.biorxiv.org/content/10.64898/2026.09.08.749421v1.supplementary-material)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_data/node:5782710/1) * [Data/Code](https://www.biorxiv.org/content/10.64898/2026.09.08.749421v1.external-links)[](https://www.biorxiv.org/panels_ajax_tab/article_tab_data_code/node:5782710/1) * [ Preview PDF](https://www.biorxiv.org/content/10.64898/2026.09.08.749421v1.full.pdf+html)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_pdf/node:5782710/1) ![Loading](https://www.biorxiv.org/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif) ## 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. ### Competing Interest Statement DPC has received financial compensation from Boston Scientific (2025) and Servier (2023). TJP reports personal fees from AstraZeneca, Canadian Pension Plan Investment Board, Chrysalis Biomedical Advisors, Illumina, Merck, and PACT Pharma and grants from Roche/Genentech outside the submitted work. RGWV is a co-founder and has equity interest in Boundless Bio. The authors declare that such activities have no relationship to the present study. ## Footnotes * * * * ## Funder Information Declared Ontario Institute for Cancer Research’s Genomics Program, Government of Ontario Synaptive and VPiX and royalties, Oxford University Press Meagan’s Walk Brainchild The Keenan Chair in Surgery, Unity Health Toronto Philanthropic funds, Gratitude 10 and the Calum Macbeth Fund Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a [CC-BY-NC-ND 4.0 International license](http://creativecommons.org/licenses/by-nc-nd/4.0/). bioRxiv and medRxiv thank the following for their generous financial support: > The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The University of Edinburgh, University of Washington, and Vrije Universiteit Amsterdam. [Donate to openRxiv ](
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