Chiche J, Pommier S, Beneteau M, Mondragón L, Meynet O, Zunino B, Mouchotte A, Verhoeyen E, Guyot M, Pagès G, Mounier N, Imbert V, Colosetti P, Goncalvès D, Marchetti S, Brière J, Carles M, Thieblemont C, Ricci JE
GAPDH enhances the aggressiveness and the vascularization of non-Hodgkin's B lymphomas via NF-κB-dependent induction of HIF-1α.
Leukemia May 2015, 29 (5) 1163-76. Deregulated expression of glycolytic enzymes contributes not only to the increased energy demands of transformed cells but also has non-glycolytic roles in tumors. However, the contribution of these non-glycolytic functions in tumor progression remains poorly defined. Here, we show that elevated expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), but not of other glycolytic enzymes tested, increased aggressiveness and vascularization of non-Hodgkin's lymphoma. Elevated GAPDH expression was found to promote nuclear factor-κB (NF-κB) activation via binding to tumor necrosis factor receptor-associated factor-2 (TRAF2), enhancing the transcription and the activity of hypoxia-inducing factor-1α (HIF-1α). Consistent with this, inactive mutants of GAPDH failed to bind TRAF2, enhance HIF-1 activity or promote lymphomagenesis. Furthermore, elevated expression of gapdh mRNA in biopsies from diffuse large B-cell non-Hodgkin's lymphoma patients correlated with high levels of hif-1α, vegf-a, nfkbia mRNA and CD31 staining. Collectively, these data indicate that deregulated GAPDH expression promotes NF-κB-dependent induction of HIF-1α and has a key role in lymphoma vascularization and aggressiveness.
More informationRubio-Patiño C, Bossowski JP, De Donatis GM, Mondragón L, Villa E, Aira LE, Chiche J, Mhaidly R, Lebeaupin C, Marchetti S, Voutetakis K, Chatziioannou A, Castelli FA, Lamourette P, Chu-Van E, Fenaille F, Avril T, Passeron T, Patterson JB, Verhoeyen E, Bailly-Maitre B, Chevet E, Ricci JE
Low-Protein Diet Induces IRE1α-Dependent Anticancer Immunosurveillance.
Cell Metab 3 Apr 2018, 27 (4) 828-842.e7. Dietary restriction (DR) was shown to impact on tumor growth with very variable effects depending on the cancer type. However, how DR limits cancer progression remains largely unknown. Here, we demonstrate that feeding mice a low-protein (Low PROT) isocaloric diet but not a low-carbohydrate (Low CHO) diet reduced tumor growth in three independent mouse cancer models. Surprisingly, this effect relies on anticancer immunosurveillance, as depleting CD8
More informationRao S, Mondragón L, Pranjic B, Hanada T, Stoll G, Köcher T, Zhang P, Jais A, Lercher A, Bergthaler A, Schramek D, Haigh K, Sica V, Leduc M, Modjtahedi N, Pai TP, Onji M, Uribesalgo I, Hanada R, Kozieradzki I, Koglgruber R, Cronin SJ, She Z, Quehenberger F, Popper H, Kenner L, Haigh JJ, Kepp O, Rak M, Cai K, Kroemer G, Penninger JM
AIF-regulated oxidative phosphorylation supports lung cancer development.
Cell Res Jul 2019, 29 (7) 579-591. Cancer is a major and still increasing cause of death in humans. Most cancer cells have a fundamentally different metabolic profile from that of normal tissue. This shift away from mitochondrial ATP synthesis via oxidative phosphorylation towards a high rate of glycolysis, termed Warburg effect, has long been recognized as a paradigmatic hallmark of cancer, supporting the increased biosynthetic demands of tumor cells. Here we show that deletion of apoptosis-inducing factor (AIF) in a Kras
More informationMondragón L, Mhaidly R, De Donatis GM, Tosolini M, Dao P, Martin AR, Pons C, Chiche J, Jacquin M, Imbert V, Proïcs E, Boyer L, Doye A, Luciano F, Neels JG, Coutant F, Fabien N, Sormani L, Rubio-Patiño C, Bossowski JP, Muller F, Marchetti S, Villa E, Peyron JF, Gaulard P, Lemonnier F, Asnafi V, Genestier L, Benhida R, Fournié JJ, Passeron T, Ricci JE, Verhoeyen E
GAPDH Overexpression in the T Cell Lineage Promotes Angioimmunoblastic T Cell Lymphoma through an NF-κB-Dependent Mechanism.
Cancer Cell 16 Sep 2019, 36 (3) 268-287.e10. GAPDH is emerging as a key player in T cell development and function. To investigate the role of GAPDH in T cells, we generated a transgenic mouse model overexpressing GAPDH in the T cell lineage. Aged mice developed a peripheral Tfh-like lymphoma that recapitulated key molecular, pathological, and immunophenotypic features of human angioimmunoblastic T cell lymphoma (AITL). GAPDH induced non-canonical NF-κB pathway activation in mouse T cells, which was strongly activated in human AITL. We developed a NIK inhibitor to reveal that targeting the NF-κB pathway prolonged AITL-bearing mouse survival alone and in combination with anti-PD-1. These findings suggest the therapeutic potential of targeting NF-κB signaling in AITL and provide a model for future AITL therapeutic investigations.
More informationRouty B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, Fidelle M, Flament C, Poirier-Colame V, Opolon P, Klein C, Iribarren K, Mondragón L, Jacquelot N, Qu B, Ferrere G, Clémenson C, Mezquita L, Masip JR, Naltet C, Brosseau S, Kaderbhai C, Richard C, Rizvi H, Levenez F, Galleron N, Quinquis B, Pons N, Ryffel B, Minard-Colin V, Gonin P, Soria JC, Deutsch E, Loriot Y, Ghiringhelli F, Zalcman G, Goldwasser F, Escudier B, Hellmann MD, Eggermont A, Raoult D, Albiges L, Kroemer G, Zitvogel L
Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.
Science 5 Jan 2018, 359 (6371) 91-97. Epub 2 Nov 2017Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients. We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance of
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