Centre de Référence Maladies Rares

U1035 INSERM

Biotherapy of genetic diseases, inflammatory disorders and cancers (BMGIC)

FR: Biologie Fondamentale Appliquée à la Médecine

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Dermatology team
Project 2.1

Contribution of bioenergetic remodeling on UVB-induced tumorigenic transformation of keratinocytes

keywords: Warburg effect, skin cancers, mitochondrial dysfunction

Description:

The most common metabolic hallmark of malignant tumors, i.e., the “Warburg effect” is their propensity to metabolize glucose to lactic acid at a high rate even in the presence of oxygen. This reliable characteristic is now used clinically to identify tumors by positron emission tomography after injection of 2-deoxy-2-(18F)fluoro-D-glucose. Since the dramatic reprogramming of energy metabolism is observed in more than 95% of advanced cancers, understanding the mechanisms and consequences of this energy metabolism alteration in cancer cells is an important challenge in cancer biology. However, almost a century after Warburg’s theory manifestation, the metabolic transformation of cancer is still a mystery. Two distinct scenarios for energy metabolism remodeling are still competing:

  1. mitochondrial dysfunction is a ‘second hit’ in the process of cancer metabolic transformation;
  2. mitochondria play a key role in tumorigenesis and their dysfunction is the driving cause of tumorigenesis.

In accordance with the first scenario, it is now clear that glucose metabolism is dramatically increased in most tumors whereas many of these tumor cells are still capable of performing oxidative phosphorylation (OXPHOS) when forced to. In these tumors, OXPHOS impairment can be the outcome of accelerated glycolysis brought about by the loss of p53 or activation of PI3K, AKT, c-MYC, and HIF, the most common alterations observed in human cancer.

In agreement with the second scenario, there are examples of tumors that exhibit inherent decreased mitochondrial functions caused by mutations in either the mitochondrial DNA (mtDNA) itself or in nuclear-encoded mitochondrial proteins. Notably, it has been demonstrated, in this decade, that the nuclear encoded tricarboxylic acid (TCA) cycle enzymes succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tumor suppressors. Besides these hereditary cancers, a large number of somatic mtDNA mutations are found in a variety of human cancers which indicates a key role of mitochondrial metabolism in oncology.

Although growing evidence indicate that mitochondria-to-nucleus retrograde signaling has an important role in tumorigenesis, most published studies reveal the importance of mitochondrial bioenergetic deficiency in the progression stage of tumorigenesis using cancer cell lines and very little information is available on the contribution of reprogramming of energy metabolism in the cancer initiation and promotion.

To analyze in-depth the contribution of bioenergetic remodeling on tumorigenic transformation, we are investigating whether pre-determined metabolic alterations could affect UVB-induced tumoral transformation of keratinocytes. This is examined through forcing the keratinocytes to use mitochondrial metabolism or, on the contrary, the glycolytic pathway for their energetic demands. To this end, we use an in vivo human epidermal reconstitution model on the back of immune-deficient mice and different transgenic mice models.

Related publications:

  • Mutations in ACTRT1 and its enhancer RNA elements lead to aberrant activation of Hedgehog signaling in inherited and sporadic basal cell carcinomas. Bal E, Park HS, Belaid-Choucair Z, Kayserili H, Naville M, Madrange M, Chiticariu E, Hadj-Rabia S, Cagnard N, Kuonen F, Bachmann D, Huber M, Le Gall C, Côté F, Hanein S, Rosti RÖ, Aslanger AD, Waisfisz Q, Bodemer C, Hermine O, Morice-Picard F, Labeille B, Caux F, Mazereeuw-Hautier J, Philip N, Levy N, Taieb A, Avril MF, Headon DJ, Gyapay G, Magnaldo T, Fraitag S, Crollius HR, Vabres P, Hohl D, Munnich A, Smahi A. Nature Medicine (2017-09-04) 2017 Sep 4. doi: 10.1038/nm.4368
  • Energy metabolism in skin cancers: A therapeutic perspective. Hosseini M, Kasraian Z, Rezvani HR. BBA Bioenergetics (2017-01) 2017, 1858(8):712-722.
  • HIF-2α protects human hematopoietic stem/progenitors and acute myeloid leukemic cells from apoptosis induced by endoplasmic reticulum stress. Rouault-Pierre K, Lopez-Onieva L, Foster K, Anjos-Afonso F, Lamrissi-Garcia I, Serrano-Sanchez M, Mitter R, Ivanovic Z, de Verneuil H, Gribben J, Taussig D, Rezvani HR, Mazurier F, Bonnet D. Cell Stem Cell. (2013-11-07) 13(5):549-63
  • Rheb regulates mitophagy induced by mitochondrial energetic status. Melser S, Chatelain EH, Lavie J, Mahfouf W, Jose C, Obre E, Goorden S, Priault M, Elgersma Y, Rezvani HR, Rossignol R, Bénard G. Cell Metab. (2013-05-07) 17(5):719-30
  • Loss of epidermal hypoxia-inducible factor-1α accelerates epidermal aging and affects re-epithelialization in human and mouse. Rezvani HR, Ali N, Serrano-Sanchez M, Dubus P, Varon C, Ged C, Pain C,Cario-André M, Seneschal J, Taïeb A, de Verneuil H, Mazurier F. J Cell Sci. (2011-12-15) 124(Pt 24):4172-83
  • HIF-1α in epidermis: oxygen sensing, cutaneous angiogenesis, cancer, and non-cancer disorders. Rezvani HR, Ali N, Nissen LJ, Harfouche G, de Verneuil H, Taïeb A, Mazurier F. J Invest Dermatol. (2011-09) 131(9):1793-805
  • Cancer cell survival following DNA damage-mediated premature senescence is regulated by mammalian target of rapamycin (mTOR)-dependent Inhibition of sirtuin 1. Back JH, Rezvani HR, Zhu Y, Guyonnet-Duperat V, Athar M, Ratner D, Kim AL. J Biol Chem. (2011-05-27) 286(21):19100-8

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