LonP1 Drives Proneural Mesenchymal Transition in IDH1-R132H Diffuse Glioma

Abstract

AbstractMalignant astroctyoma and glioblastoma are diffuse CNS tumors that have markedly similar features, including microvascular proliferation and necrosis, and the latter presents higher grade and poorer survival. The Isocitrate dehydrogenase 1/2 (IDH) mutation further predicts improved survival and is present in oligodendroglioma and astrocytoma. The latter are more prevalent in younger populations with a median age of 37 years at diagnosis as compared to glioblastoma with a median age of 641,2. These tumors frequently have co-occurring ATRX and/or TP53 mutations (Brat et al., 2021). The IDH mutation is known to cause dysregulation of the hypoxia response broadly in CNS tumors and subsequent reduction in both tumor growth and treatment resistance. The frequency of tumor recurrence is high for diffuse CNS tumors. Understanding the mechanism and potential molecular targets enhancing treatment resistance and local invasion in IDH mutant diffuse glioma is necessary for developing new treatment strategies for better tumor control and improving overall survival. Recent evidence highlights the importance of local foci in IDH mutant glioma with an accelerated stress response as responsible for recurrence in these tumors. Here, we demonstrate that LonP1 drives NRF2 and subsequent proneural mesenchymal transition interdependent with the IDH mutation in response to stress and other tumor microenvironment cues. Our findings provide further evidence that targeting LonP1 may be a crucial strategy for improving the standard-of-care treatment in IDH mutant diffuse astrocytoma.Data Access StatementResearch data supporting this publication are as presented in the manuscript.Key PointsLonP1 drives proneural mesenchymal transition in IDH1 mutant astrocytoma in response to hypoxia and subsequent reoxygenationThe ability of LonP1 to drive proneural mesenchymal transition is interdependent with the presence of the IDH1 mutationLonP1 expression is a predictor for enhanced upregulation of mesenchymal features on a single cell basis and is correlated with genetic modules that have poorer survivalImportance of StudyThe IDH mutant astrocytoma have poor survival and little is known about the genetic and microenvironmental cues driving disease progression. Most IDH mutant astrocytoma occur as low grade gliomas and then upon recurrence develop into high grade gliomas. At lower grades, cellular foci with elevated hypoxic features are observed following treatment with the standard-of-care, Temozolomide. The IDH1-R132H mutation occurs in 90% of cases where a IDH mutation occurs. Here, we interrogated several single cell datasets and the TCGA dataset to demonstrate the importance of LonP1 in driving genetic modules with elevated Wnt Signaling that were associated with the infiltrative niche and poor overall survival. We also report findings that demonstrate the interdependence of LonP1 and the IDH1-R132H mutation in driving enhanced proneural-mesenchymal transition in response to oxidative stress. These findings may lead to further work understanding the importance of LonP1 and the tumor microenvironment in driving tumor recurrence and disease progression in IDH1 mutant astrocytoma.