Transformation Foci in IDH1-mutated Gliomas Show STAT3 Phosphorylation and Downregulate the Metabolic Enzyme ETNPPL, a Negative Regulator of Glioma Growth

Abstract

IDH1-mutated gliomas are slow-growing brain tumours which progress into high-grade gliomas. The early molecular events causing this progression are ill-defined. Previous studies revealed that 20% of these tumours already have transformation foci. These foci offer opportunities to better understand malignant progression. We used immunohistochemistry and high throughput RNA profiling to characterize foci cells. These have higher pSTAT3 staining revealing activation of JAK/STAT signaling. they downregulate RnAs involved in Wnt signaling (DAAM2, SFRP2), eGfR signaling (MLC1), cytoskeleton and cell-cell communication (EZR, GJA1). in addition, foci cells show reduced levels of RnA coding for Ethanolamine-Phosphate Phospho-Lyase (ETNPPL/AGXT2L1), a lipid metabolism enzyme. etnppL is involved in the catabolism of phosphoethanolamine implicated in membrane synthesis. We detected etnppL protein in glioma cells as well as in astrocytes in the human brain. its nuclear localization suggests additional roles for this enzyme. ETNPPL expression is inversely correlated to glioma grade and we found no etnppL protein in glioblastomas. overexpression of etnppL reduces the growth of glioma stem cells indicating that this enzyme opposes gliomagenesis. collectively, these results suggest that a combined alteration in membrane lipid metabolism and STAT3 pathway promotes IDH1-mutated glioma malignant progression. Diffuse low-grade gliomas (DLGG, WHO grade II) is a subtype of glial brain tumours typically affecting young patients in their third or fourth decades 1. Compared to glioblastomas, much less is known about these tumours. They are mostly found in the brain white matter and are probably derived from transformation of oligodendrocyte progenitors which are the main proliferative cell population in the brain. They are most often found in functional brain areas such as the motor cortex, Broca's area, frontal lobe and insula. Histologically, diffuse low-grade

Identification of CRYAB+KCNN3+SOX9+astro-like and EGFR+PDGFRA+OLIG1+oligo-like tumoral cells in diffuse low-grade gliomas and implication of Notch1 signalling in their genesis

“…This heterogeneity is also supported by two recent single cell RNA seq studies [21,22]. Additionally, we reported that approximately 20% of DLGG have transformation foci with cells showing a high level of activated STAT3 pathway and reduced level of a lipid metabolism enzyme, ETNPPL [23]. One consequence of this cellular heterogeneity is that current treatments may only target sub-populations of cells while leaving other cell types unaffected and prone to tumor relapse.…”

The Role and Therapeutic Targeting of JAK/STAT Signaling in Glioblastoma

“…Finally, overexpression of TGF-β-related protein Smad6 in nearly 90% of GBM tissues promotes the ubiquitination and subsequent degradation of the STAT3 inhibitor PIAS3 [ 41 , 42 , 43 ]. As a consequence of these aforementioned mechanisms, the reported frequency of phospho-Tyr-STAT3 positivity in human glioma samples ranges up to 60% and has been significantly correlated with histologic grade, EGFRvIII positivity, aggressive behavior, and poor prognosis [ 44 , 45 , 46 , 47 , 48 , 49 ]. Recent work has affirmed the negative prognostic significance of upregulation of JAK/STAT gene targets—e.g., cytokines, cytokine receptors, and JAKs—in the classical subtype of GBM [ 50 ].…”

Megalencephalic leukoencephalopathy with subcortical cysts 1 (MLC1) promotes glioblastoma cell invasion in the brain microenvironment

“…A prior report has linked MLC1 to the expression levels of another receptor tyrosine kinase, EGFR, in cultured astrocytes [ 39 ]. MLC1 has more recently been linked to EGFR signaling in low-grade human gliomas harboring R132H mutations in the IDH1 gene [ 40 ]. Hence, it is enticing to speculate the loss of MLC1 in GBM cells causes an imbalance in receptor tyrosine kinase expression and/or signaling, leading to a transition from a mesenchymal to an epithelial-like morphology with diminished growth and invasion.…”