Metabolic and tumorigenic adaptation in mesenchymal stromal cells : a new bioswitch function for the glucose-6-phosphate translocase

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RATIONALE : Molecular markers associated with mesenchymal stromal cells (MSC) are thought to characterize the brain tumor-initiating cells involved in the development of glioblastoma, the most common and aggressive primary brain cancer. These findings suggest that a subset of primary glioblastomas may derive from transformed stem cells upon their recruitment within the tumors' environment. This evidence implies that circulating MSC must respond to tumor-derived growth factor cues and therefore cross the blood-brain barrier (BBB), but more importantly that MSC must also adapt metabolically to the low oxygen environment and to nutrient deprivation that characterizes hypoxic tumors. From our last NSERC-funded program, we have identified the endoplasmic reticulum-embedded glucose-6-phosphate transporter (G6PT) as a potential metabolic regulator of MSC mobilization to brain tumors. Indeed, G6PT's powerful inhibitors such as mumbaistatin analogs and chlorogenic acid led to significant decrease in several steps involved in tumorigenesis such as MSC chemotactic response to tumor-derived growth factors, cancer cells proliferation, cell cycle division, and extracellular matrix degradation. Altogether, this evidence supports a new role for G6PT in tumorigenesis through yet undefined mechanisms. LONG TERM OBJECTIVE : To increase our comprehension at the molecular level of the new role of G6PT dictating the adaptative, metabolic and chemotactic control of MSC in tumorigenesis. NOVELTY AND EXPECTED SIGNIFICANCE : We are convinced that our study will provide the first demonstration for G6PT's new role as a potential signal transducing protein in stem cells differentiation and as a regulator in the ability of MSC to cross the BBB. The control of these G6PT-mediated biological mechanisms may ultimately also help understand MSC biodistribution in vivo in response to different microenvironment cues. Moreover, the characterisation and regulation of G6PT in MSC opens up the possibility to link metabolic glucose-sensing and tumor-promoting mechanisms that can both be potentially targeted by viable anti-diabetic and anti-cancer agents.