A new function of mTOR with implications for LAM cell growth and, perhaps, treatment
BY ISSAM BEN-SAHRA, PHD, AND BRENDAN MANNING, PHD, HARVARD T.H. CHAN SCHOOL OF PUBLIC HEALTH, BOSTON, MA
The "mTOR and nucleotide" team in the Brendan Manning lab.
From the left to the right: Brendan Manning, PhD, Gerta Hoxhaj, PhD, Jessica Howell, PhD, and Issam Ben-Sahra, PhD.
In an ongoing series of studies in our lab over the past 4 years, funded in part by a generous LAM Foundation Postdoctoral Fellowship to Issam, we set out to define the metabolic changes that occur when mTOR is activated both physiologically in normal cells and pathologically, upon loss of function of the tuberous sclerosis complex (TSC) genes, which underlies the development of LAM. These studies, which Issam lead in collaboration with two other postdoctoral fellows from the lab, Jessica Howell and Gerta Hoxhaj, made an important new discovery regarding the cellular functions of mTOR that contribute to its role in promoting cell growth. In two separate papers in Science1, 2, the most recent being published this February, we describe two previously unknown functions for mTOR that stimulate the synthesis of nucleotides, the building blocks for our genetic material RNA and DNA.
Cells in our body can be stimulated to grow and make more cells, such as during normal developmental growth, during the healing of wounds, and upon activation of immune cells in response to pathogens. Our recent studies establish important new mechanisms by which growth signals, relayed through the TSC-mTOR pathway, control the synthesis of the two classes of nucleotides, pyrimidines1 and purines2, essential for duplication of our genetic material as DNA during cell division. This work, coupled to previous studies establishing the role of mTOR in promoting protein and lipid synthesis, demonstrates that mTOR is a master regulator of biosynthetic metabolism, linking growth signals to the synthesis of the major materials needed to build more cells and bigger cells.
While our studies show that this is a new function of mTOR occurring in all growing cells, we also demonstrate that upon loss of the TSC proteins and its inhibitory activity toward mTOR, nucleotides and other macromolecules are synthesized in an uncontrolled manner. Loss of control over mTOR and these biosynthetic processes is what underlies the uncontrolled growth of LAM cells and the majority of cancer cells, which also exhibit mTOR activation. More specifically, our study suggests that uncontrolled mTOR signaling in LAM and TSC cells contributes to the unrestrained growth of these cells, at least in part, by increasing the nucleotide pool required to meet an increased demand for RNA and DNA in these growing cells. While we show that mTOR inhibitors such as rapamycin (sirolimus) block these new functions of mTOR, ongoing studies in our lab are testing the possibility that directly inhibiting nucleotide synthesis with available clinically safe compounds offers a therapeutic approach to LAM and TSC that is an alternative to mTOR inhibitors.
 Ben-Sahra I*, Hoxhaj G*, Ricoult SJH, Asara JM, Manning BD. mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science 12 Feb 2016:
Vol. 351, Issue 6274, pp. 728-733 DOI: 10.1126/science.aad0489
 Ben-Sahra I*, Howell JJ*, Asara JM, Manning BD. Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science. 2013 Mar 15;339(6125):1323-8. doi: 10.1126/science.1228792. Epub 2013 Feb 21.