Mechanisms of uncoupling cellular growth from mTOR pathway activity

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Cellular growth and timing of division is coordinated and regulated through specific signalling pathways, growth factors, availability of nutrients and energy status. This is paramount for embryonic development, stem cell maintenance, tissue morphogenesis and homeostasis. All eukaryotic organisms (their cells have a nucleus) contain a kinase known as the mechanistic Target of Rapamycin (mTOR) that senses multiple factors such as nutrients and growth factors availability. In the presence of the above, mTOR promotes basic cellular processes such as protein translation and basic metabolism of lipids and carbohydrates and instructs cells to grow in mass and numbers. Inhibition of mTOR through genetic or pharmacological means has a profound negative effect on cell growth. Mutated and overactivated mTOR kinase forms are implicated in many cancers. Numerous clinical trials are currently ongoing targeting the kinase. However, cells (including cancer cells) can rewire their metabolism and resume growth in states where mTOR is inhibited. This shows that there are mechanisms of bypassing the requirement of mTOR for growth and essentially uncoupling nutrient and growth factor availability from cell division. Nevertheless, these mechanisms have remained elusive. We have identified 102 genes, conserved between fission yeast and humans, that when mutated, cells can bypass mTOR inhibition and continue growing and dividing. These genes point to specific processes within eukaryotic cells. Our aim is to comprehensively analyse the roles and connections of all these genes using cutting edge genetic, molecular biology and computational approaches. Our aim is to form a complete genetic connectivity roadmap that will reveal the molecular mechanisms that are involved in inhibition of mTOR resistance. Our results will directly point towards possible vulnerabilities of resistant cells that can be further exploited in cancer biology and beyond.