Mechanisms of uncoupling cellular growth from mTOR pathway activity

细胞的生长和分裂是通过特定的信号通路、生长因子、营养物质的可利用性和能量状态来协调和调节的。这对胚胎发育、干细胞维持、组织形态发生和体内平衡至关重要。所有真核生物（它们的细胞都有细胞核）都含有一种被称为雷帕霉素机械靶蛋白（mTOR）的激酶，它能感知多种因素，如营养物质和生长因子的可用性。在上述存在的情况下，mTOR促进基本的细胞过程，如蛋白质翻译和脂质和碳水化合物的基本代谢，并指导细胞在质量和数量上生长。通过遗传或药理学手段抑制mTOR对细胞生长有深远的负面影响。突变和过度激活的mTOR激酶形式与许多癌症有关。目前正在进行针对该激酶的大量临床试验。然而，在mTOR被抑制的状态下，细胞（包括癌细胞）可以重新连接它们的代谢并恢复生长。这表明有一些机制可以绕过生长对mTOR的要求，并从细胞分裂中分离营养和生长因子的可用性。然而，这些机制仍然难以捉摸。我们已经确定了102个基因，在裂变酵母和人类之间保守，当突变时，细胞可以绕过mTOR抑制，继续生长和分裂。这些基因指向真核细胞内的特定过程。我们的目标是全面分析所有这些基因的作用和连接使用尖端的遗传，分子生物学和计算方法。我们的目标是形成一个完整的遗传连接路线图，将揭示参与抑制mTOR抗性的分子机制。我们的研究结果将直接指出耐药细胞可能存在的弱点，这些弱点可以在癌症生物学和其他领域进一步利用。

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.