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Preprint WatchMildJune 5th, 2026

Spatially confined niches support hypoxia-associated transcriptional plasticity contributing to malignant progression in IDH-mutant gliomas

Das, D.; Pandele, A.; Jariwala, V. D.; Ghariwala, N. S.; Mohammed, A. O.; Das, T.; Krolla, C.; Arosh, S. M.; Hossain, N.; Shhab, M. A.; Hosen, I.; Smith, S. J.; Grauvogel, J.; Vasilikos, I.; Roelz, R.; Nakgawa, J.; Hoefllin, R.; Tirosh, I.; Juratli, T.; Schneider, M.; Prinz, M.; Hervey-Jumper, S.; Rahman, R.; Boerries, M.; Beck, J.; Jospeh, K.; Andrieux, G.; Ravi, V. M.; Chakraborty, S.

Microglia drive a quiescent-to-activated transition in IDH-mutant glioma stem-like cells by enhancing HBEGF/EGFR paracrine signaling, and elevated EGFR-driven signaling marks malignant progression.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

This preprint positions EGFR as an active driver of malignant progression in IDH-mutant glioma, where microglia-derived HBEGF sustains EGFR paracrine signaling and pushes quiescent astrocyte-like tumor cells into a proliferative state (bioRxiv 10.64898/2026.05.31.729105). The single indexed EGFR failure in the Claidex graph is bg-60366-egfr-cdac-nsclc-strategic-shutdown, an EGFR-directed program in EGFR-mutant non-small cell lung cancer that ended on a sponsor decision rather than on biology. The preprint neither contradicts nor rescues that program, because it concerns a different tumor context and a paracrine ligand axis rather than oncogenic EGFR mutation. It does reinforce that EGFR pathway activity remains a live progression mechanism across tumor types, which keeps the rationale for EGFR-directed approaches intact even where one modality was shelved for portfolio reasons. Severity is MILD because only one EGFR failure is on file and that failure was an operational shutdown, not an efficacy signal.

Abstract excerpt

Background While hypoxia is a well-established driver of glioblastoma progression, its role in IDH-mutant gliomas, characterized by localized hypoxic microenvironments rather than overt necrosis, remains poorly understood. Here, we investigate how hypoxia and microenvironmental-adaptations shape cellular heterogeneity and transcriptional plasticity in these tumors. Methods We integrated bulk, single-cell, and spatial-transcriptomics datasets from IDH-mutant glioma patients (Astrocytomas and Oligodendrogliomas) to characterize cellular-states and map the localization of hypoxic niches. To uncover tumor microenvironment effects, we established co-culture models using primary IDH-mutant glioma cells with human microglia and astrocytes, maintained under hypoxic and normoxic conditions, followed by bulk RNA-sequencing. Results We identified a hypoxia-associated astrocyte-like (AC-like) program that defines a quiescent, non-cycling population with a distinct transcription factor profile indicative of functional plasticity in IDH-mutant gliomas. These cells harbor glioma stem cell (GSC)-like features and are poised for a quiescent-to-activated (Q-to-A) transition that drives tumor progression. Mechanistically, co-culture models reveal that microglia promote this Q-to-A transition by enhancing HBEGF/EGFR paracrine signaling. Spatial transcriptomics uncovers the co-localization of hypoxic niches within quiescent AC-like cells, whereby the activated subpopulation forms discrete niches defined by localized HBEGF/EGFR communication gradients. Notably, tumors exhibiting elevated EGFR-driven activation signatures correlate with higher histological grade and poorer patient survival, implicating the Q-to-A transition as a critical driver of malignant progression. Conclusion Q-to-A transition within the hypoxic niche represents a critical driver of malignant progression in IDH-mutant gliomas, providing a microenvironment-driven mechanism for the transition to higher-grade disease and identifying targetable-vulnerabilities for therapeutic intervention.

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1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.