Académie royale de Médecine de Belgique

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Prix Alvarenga de Piauhy 2014 - Lauréat Paolo Ettore Porporato (Présentation + résumé)

Présentation du Pr Arsène Burny, membre honoraire

Role of mitochondrial superoxide targeting on tumor signaling and metastasis prevention


L’effet Warburg, décrit en 1926 montre la dependance des tumeurs à l’égard du lactate produit par la fermentation du glucose. Les séquençages à haut débit, montrant des mutations dans des gènes du métabolisme oxydatif, permettent d’identifier de nouvelles cibles de traitement et replace le métabolisme à la position centrale qui est la sienne.

Deux exemples illustreront ce bref propos :

-1) Les mutations de l’isocitrate déshydrogénase (IDH) (affectant surtout une arginine R mutée en H,G, C, S, L) conduisent à la production massive (50 à 100 fois la quantité normale, donc détectable)  de 2-hydroxyglutarate au lieu de 2-cétoglutarate. Or, ce dernier est le co-facteur de dioxygénases, enzymes catalysant la déméthylation d’histones, d’acides nucléiques, de protéines cytoplasmiques… Ces réactions sont cruciales dans la régulation d’expression des gènes. Il s’ensuit une perturbation importante de ce programme.

Intérêt pharmaceutique : diagnostic assez facile de la mutation et mise au point d’inhibiteurs spécifiques de l’isocitrate déshydrogénase mutée.

Intérêt médical : mutations rencontrées dans les gliomes de bas grade, glioblastomes, leucémies aiguës, myéloblastiques et lymphoblastiques.


-2) La souris porteuse d’une tumeur du pancréas, dépendante de l’oncogène Ki-rasG12D sous le contrôle d’une tétracycline (la doxycycline). Arrêter le traitement doxycycline entraîne la régression temporaire de la tumeur  La rechute ne peut cependant être évitée que par le traitement par l’oligomycine, inhibiteur de la chaîne de transport des électrons, produits du métabolisme vers l’oxygène. Les cellules cancéreuses qui survivent à l’élimination de l’oncogène ont des caractéristiques de cellules souches dormantes  et sont des cellules qui respirent !

Ces deux exemples illustrent l’importance du métabolisme énergétique pour la cellule cancéreuse, sa survie, ses adaptations et les perspectives de traitement possibles

Références :

1) Cancer-associated isocitrate dehydrogenase mutations. KE Yen et DP Schenken, The Oncologist 2012, 17,5-8.

-2) Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. A. Viale et al, Nature 2014,514,628-632.

P. Ett. Porporato: Role of mitochondrial superoxide targeting on tumor signaling and metastasis prevention

Energy metabolism is essential to cancer development and progression. Indeed, tumors require high-rate energy production to sustain grow and resist to apoptosis, therefore cancer metabolism is nowadays considered a hallmark of cancer (1, 2). The main metabolic alteration in cancer cells, promoting proliferation and resistance to stress, is the so-called Warburg effect defined as the increase in glucose consumption even in presence of oxygen (i.e. aerobic glycolysis) (2), which is currently an appealing target for therapy (1).  However, aside proliferation and survival, there is still a limited understanding of the impact of metabolic reprogramming in mediating other biological processes.
To this aim, we decided to investigate the metabolic requirements of invasion and metastasis. Indeed, metastasis prevention is currently a main challenge in cancer therapy considering that 90% of cancer patients dies of metastatic disease (3).
Despite the importance of aerobic glycolysis in cancer, we uncovered a central role of mitochondrial metabolism in mediating metastatic progression (4).
Through the generation of several cancer cell lines differing only for their metastatic potential, we identified that the acquisition of metastatic capability was always associated with alterations of the mitochondrial metabolism. Not a single metabolic switch was present, but a wide array, ranging from increased oxygen consumption rate to a slight decrease. Despite the variability in the mitochondrial phenotype, in all metastatic cells tested, the occurring change in the rate oxygen consumption resulted in an increased production rate of mitochondrial ROS (mtROS).  
Despite mitochondrial ROS are often considered a byproduct of mitochondrial metabolism simply promoting cell death induction (5), emerging results support their role as a signaling agent. In fact, we found that in our system a moderate increase in mtROS is acting as a signaling molecule and, in particular, it is sufficient to promote Src and Pyk2 activation with a pathway reminiscent of the one stimulated by TGFβ(4). Importantly, reducing mtROS by targeted antioxidant such as mitoTEMPO or mitoQ, specific for mitochondria, was sufficient to prevent metastasis dissemination in mice, both with human and murine cells. Interestingly, a well-known stimulus of mtROS production is glucose starvation, a condition normally occurring in tumors because of the Warburg phenotype (6). Accordingly to the previous results, we found that glucose deprivation-derived mtROS promoted tumor cell migration dependent on the upregulation of MCT1, a protein responsible for lactate uptake. Importantly, lactate was sufficient to prevent cellular migration in this condition, by providing a different energy supply. These data highlights the role of mtROS as signaling agents sensing energy depletion and promoting utilization of different oxidative fuels, or ultimately tumor cell migration during extreme deprivation conditions. Collectively, this works shows the importance of mtROS as signaling agents and the potential for targeting metastasis prevention.

Reference: (1) Porporato PE, et al. Anticancer targets in the glycolytic metabolism of tumors: a comprehensive review. Front Pharmacol 2011;2:49.

(2) Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646-74.

(3) Gupta GP, Massague J. Cancer metastasis: building a framework. Cell 2006;127:679-95.

(4) Porporato PE, et al. A Mitochondrial Switch Promotes Tumor Metastasis. Cell Rep 2014;8:754-66.    

(5)     Porporato P, Sonveaux P. Paving the way for therapeutic prevention of tumor metastasis with agents targeting mitochondrial superoxide. Molecular & Cellular Oncology 2015e968043

(6) De Saedeleer CJ, Porporato PE, et al. Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration. Oncogene 2014;33:4060-8.