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.

Details

Title
Transformation Foci in IDH1-mutated Gliomas Show STAT3 Phosphorylation and Downregulate the Metabolic Enzyme ETNPPL, a Negative Regulator of Glioma Growth
Author
Leventoux, N 1   VIAFID ORCID Logo  ; Augustus, M 2 ; Azar, S 2 ; Riquier, S 3 ; Villemin J P 4 ; Guelfi, S 2 ; Falha, L 2 ; Bauchet, L 5 ; Gozé, C 6 ; Ritchie, W 4   VIAFID ORCID Logo  ; Commes, T 3 ; Duffau, H 5   VIAFID ORCID Logo  ; Rigau, V 7   VIAFID ORCID Logo  ; Hugnot, J P 8 

1  Institute for Neurosciences of Montpellier, Institut National de la Santé et de la Recherche Médicale (INSERM). U1051 - Hôpital Saint-Éloi, 80 Avenue Augustin Fliche - 34091 Montpellier cedex 5, Montpellier, France (GRID:grid.464046.4) (ISNI:0000 0004 0450 3123); Keio University School of Medicine, Physiology Department. 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan (GRID:grid.26091.3c) (ISNI:0000 0004 1936 9959) 
2  Institute for Neurosciences of Montpellier, Institut National de la Santé et de la Recherche Médicale (INSERM). U1051 - Hôpital Saint-Éloi, 80 Avenue Augustin Fliche - 34091 Montpellier cedex 5, Montpellier, France (GRID:grid.464046.4) (ISNI:0000 0004 0450 3123) 
3  Institute for Regenerative Medicine & Biotherapy, Hôpital Saint-Éloi, 80 Avenue Augustin Fliche - 34091 Montpellier cedex 5, Montpellier, France (GRID:grid.414352.5) 
4  Institute of Human Genetics, Centre National de la Recherche Scientifique (CNRS). UMR9002, 141 rue de la Cardonille, Montpellier, France (GRID:grid.462268.c) (ISNI:0000 0000 9886 5504) 
5  Institute for Neurosciences of Montpellier, Institut National de la Santé et de la Recherche Médicale (INSERM). U1051 - Hôpital Saint-Éloi, 80 Avenue Augustin Fliche - 34091 Montpellier cedex 5, Montpellier, France (GRID:grid.464046.4) (ISNI:0000 0004 0450 3123); Neurosurgery Department. Hôpital Gui de Chauliac, 80 Avenue Augustin Fliche, Montpellier, France (GRID:grid.414130.3) (ISNI:0000 0001 2151 3479) 
6  Institute for Neurosciences of Montpellier, Institut National de la Santé et de la Recherche Médicale (INSERM). U1051 - Hôpital Saint-Éloi, 80 Avenue Augustin Fliche - 34091 Montpellier cedex 5, Montpellier, France (GRID:grid.464046.4) (ISNI:0000 0004 0450 3123); Laboratory of Solid Tumors Biology. Hôpital Lapeyronie, 371 Avenue du Doyen Giraud, Montpellier, France (GRID:grid.464046.4) 
7  Institute for Neurosciences of Montpellier, Institut National de la Santé et de la Recherche Médicale (INSERM). U1051 - Hôpital Saint-Éloi, 80 Avenue Augustin Fliche - 34091 Montpellier cedex 5, Montpellier, France (GRID:grid.464046.4) (ISNI:0000 0004 0450 3123); Department of Pathology and Oncobiology. Hôpital Gui de Chauliac, 80 Avenue Augustin Fliche, Montpellier, France (GRID:grid.464046.4) 
8  Institute for Neurosciences of Montpellier, Institut National de la Santé et de la Recherche Médicale (INSERM). U1051 - Hôpital Saint-Éloi, 80 Avenue Augustin Fliche - 34091 Montpellier cedex 5, Montpellier, France (GRID:grid.464046.4) (ISNI:0000 0004 0450 3123); University of Montpellier, Place Eugène Bataillon, Montpellier, France (GRID:grid.121334.6) (ISNI:0000 0001 2097 0141) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-020-62145-1
ProQuest document ID
2383478639
Copyright
This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.