The TSC-mTORC1 Network Controls Bicarbonate Uptake to Support Cell Growth

In LAM, abnormal muscle-like cells in specific organs or tissues grow out of control, especially the lungs, lymph nodes, and kidneys. Over time, these LAM cells can grow throughout the lungs and destroy the normal lung tissue inducing respiratory failure. This disease is mainly due to a loss of a protein called TSC (Tuberous Sclerosis Complex), leading to hyperactivation of a protein called mTOR (mammalian Target Of Rapamycin). Currently, there are no effective treatments against LAM. mTOR is widely activated in most cancers, leading to increased energy intake in cancer and LAM cells. The alteration of small molecules called metabolites in TSC-deficient cells could explain the abnormal proliferation of cells in LAM and cancer disease. In our research project, we observed that the molecule bicarbonate was stimulated by mTOR and increased in LAM cells. Bicarbonate is metabolically consumed to support the cellular biomass required for cell proliferation. Therefore, we hypothesized that targeting the metabolic enzyme under the control of mTOR that enables the accumulation of bicarbonate would eliminate the growth of LAM cells. Firstly, we will determine the global change in cellular metabolism in LAM cells by performing metabolomics experiments using the mass spectrometry instrument. Then, by using specific inhibitors targeting bicarbonate metabolism, we will determine whether bicarbonate could be exploited to target the pathophysiology of LAM.