Activities

The research of our group aims at elucidating the molecular mechanisms regulating epithelial stem cell (SC) self-renewal, differentiation and stress response, with specific focus on the mTOR/Akt signaling.We have established that in limbal epithelial stem cells (LESCs), a SC type used in transplantation therapies for corneal regeneration, Akt signaling is prominent in SC populations both in vivo and in vitro, and that Akt1 promotes while Akt2 opposes SC self-renewal (Saoncella S. et al., Stem Cells, 2014).
Loss of Akt2 signaling enhances LESC maintenance ex vivo, whereas Akt1 depletion anticipates SC exhaustion. Mechanistically, the antagonistic functions of Akt1 and Akt2 in SC control are mainly dictated by their differential subcellular distribution, being nuclear Akt2 selectively implicated in FOXO transcription factors inhibition. Akt2 down-regulation favors LESC maintenance as a result of a gain of FOXO functions, which in turn attenuates the mechanistic target of rapamycin complex one (mTORC1) activity, thereby preventing SC differentiation and/or senescence.
Considering that SC depletion represents the main cause of failure of LESC transplantation therapies, our work may have translational implications as it suggests that the Akt2/FOXO/mTOR signaling axis may represent a druggable target for ameliorating LESC cell expansion in clinical settings.
More recently we have discovered that in epidermal cells, loss of Rictor, an essential component of the mechanistic target of rapamycin complex 2 (mTORC2), surprisingly leads to increased keratinocyte lifespan, protection from senescence, and enhanced tolerance to cellular stressors causing oxidative damage, both in vitro  and in vivo (Tassone B. et. al., Cell Death Differ., 2017). Rictor-deficient keratinocytes exhibit changes in global gene expression profiles consistent with metabolic alterations and enhanced stress tolerance, a shift in cell catabolic processes from glycids and lipids to glutamine consumption, and increased production of mitochondrial reactive oxygen species (ROS). Mechanistically, the resiliency of Rictor-deficient epidermal cells relies on these ROS increases, indicating the occurrence of a process of stress adaptation known as as mitohormesis. Since oxidative stress is a key determinant of SC senescence, our data suggest that manipulation of Rictor/mTORC2 functions may help preventing the functional decline of epidermal SC typically associated with aging. Considering that adaptation to oxidative stress plays a key role in the resistance of tumors to oncotherapies, our recent activity aims at testing the hypothesis that the “mitohormetic” behavior described in epidermal cells following Rictor/mTORC2 loss may participate to the establishment of cancer progression and therapeutic resistance. We are currently exploring these concepts in melanoma cells and breast cancer SCs. The latter project relies on an ongoing collaboration with the team of Prof. Federica Cavallo, which consists in the design and optimization of anti-cancer vaccines aimed against the amino acid transporter SLC7A11/xCT, which plays a key role in the adaptation of breast cancer (stem) cells to oxidative stress, and whose biological activity is regulated by the mTORC2/Akt axis. Our main hypothesis is that manipulation of mTORC2 activity may synergize with vaccination in eradicating tumor-initiating cell populations.

Group

• Prof. Enzo Calautti (PI)
• Luca Ponzone (Master Degree Student):
• Elena Gallo (Master degree Student):
• Roberto Ruiu (Post-Doc):