Keratinocyte stem cells play a fundamental role in homeostasis and repair of stratified epithelial tissues. Transplantation of cultured keratinocytes autografts provides a landmark example of successful cellular therapies by restoring durable integrity in stratified epithelia lost to devastating tissue conditions. Despite the overall success of such procedures, failures still occur in case of paucity of cultured stem cells in therapeutic grafts. Strategies aiming at a further amplification of stem cells during keratinocyte ex vivo expansion may thus extend the applicability of these treatments to subjects in which endogenous stem cells pools are depauperated by aging, trauma, or disease. Pharmacological targeting of stem cell signaling pathways is recently emerging as a powerful strategy for improving stem cell maintenance and/or amplification. Recent experimental data indicate that pharmacological inhibition of two prominent keratinocyte signaling pathways governed by apical mTOR and ROCK protein kinases favor stem cell maintenance and/or amplification ex vivo and may improve the effectiveness of stem cell-based therapeutic procedures. In this review, we highlight the pathophysiological roles of mTOR and ROCK in keratinocyte biology and evaluate existing pre-clinical data on the effects of their inhibition in epithelial stem cell expansion for transplantation purposes.
Malignant melanoma represents the most fatal skin cancer due to its aggressive behavior and high metastatic potential. The introduction of BRAF/MEK inhibitors and immune-checkpoint inhibitors (ICIs) in the clinic has dramatically improved patient survival over the last decade. However, many patients either display primary (i.e., innate) or develop secondary (i.e., acquired) resistance to systemic treatments. Therapeutic resistance relies on the rewiring of multiple processes, including cancer metabolism, epigenetics, gene expression, and interactions with the tumor microenvironment that are only partially understood. Therefore, reliable biomarkers of resistance or response, capable of facilitating the choice of the best treatment option for each patient, are currently missing. Recently, activation of nicotinamide adenine dinucleotide (NAD) metabolism and, in particular, of its rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT) have been identified as key drivers of targeted therapy resistance and melanoma progression. Another major player in this context is the mammalian target of rapamycin (mTOR) pathway, which plays key roles in the regulation of melanoma cell anabolic functions and energy metabolism at the switch between sensitivity and resistance to targeted therapy. In this review, we summarize known resistance mechanisms to ICIs and targeted therapy, focusing on metabolic adaptation as one main mechanism of drug resistance. In particular, we highlight the roles of NAD/NAMPT and mTOR signaling axes in this context and overview data in support of their inhibition as a promising strategy to overcome treatment resistance.
mTORC2 regulates a variety of vital cellular processes, and its aberrant functioning is often associated with various diseases. Rictor is a peculiar and distinguishing mTORC2 component playing a pivotal role in controlling its assembly and activity. Among living organisms Rictor is conserved from unicellular eukaryotes to metazoan. We replaced two distinct, but conserved, glycines in both the Dictyostelium piaA gene and its human ortholog, rictor. The two conserved residues are spaced by approximately 50 aminoacids and both are embedded within a conserved region falling in between the Ras-GEFN2 and Rictor_V domains. The effects of point mutations on the mTORC2 activity and integrity were assessed by biochemical and functional assays.In both cases, the reciprocal exchange between mammals and Dictyostelium rictor and piaA gene point mutations impaired mTORC2 activity and integrity.Our data indicate that the two Gly residues are essential for the maintenance of mTORC2 activity and integrity in organisms that appear to be distantly related, suggesting a primeval role in the assembly and proper TOR complex 2 functioning.
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