BLRD Research Career Scientist Award Application

Cancer cells reprogram their metabolism to fuel anabolic processes required for their proliferation and survival. One way by which cancer cells reprogram metabolism is by hijacking the evolutionarily conserved metabolic function of the PI3K/Akt/mTORC1 signaling pathway. Another way is by markedly elevating the expression of the hexokinase isoform, HK2, which catalyzes the first committed step in glucose metabolism. The long-term goal of this grant application is to overcome challenges in targeting cancer metabolism and Akt for cancer therapy. Although cancer cells can be selectively detected because of their high glucose metabolism (FDG-PET scan), exploiting this property for selective targeting is challenging because interference with glucose metabolism could have adverse consequences. We overcame this roadblock by showing that hexokinase 2, which catalyzes the first committed step in glycolysis, and is selectively expressed in cancer cells, can be systemically deleted in mice without any adverse consequences. The proposal is based on findings made in my laboratory at the cellular and organismal levels, and address the following paradigm shifts: (i) Germ-line deletion of hexokinase 2, which is markedly elevated in cancer cells, is embryonic lethal. However, we found that its systemic deletion in adult mice is well tolerated, and therapeutic in several mouse models of cancer. We identified a role of hexokinase 2 (HK2) in EMT and metastasis through a novel mechanism which is independent of its kinase activity. Recently we showed that Hk2 is required for liver fibrosis through mediating histone lactylation. We will continue investigating this observation to find therapeutic approaches to treat liver fibrosis and consequently MASH-induced HCC. (ii) The inhibition of AMPK is considered pro-tumorigenic. Paradoxically, we found that AMPK activation is required for cell survival during solid tumor formation and metastasis. The role of AMPK in metastasis is dependent, at least in part, on the induction of the fatty acids translocator CD36 expression. We will delineate the role of AMPK during metastasis in human cells and mouse models of breast and prostate cancer. We anticipate that the proposed studies will uncover new mechanisms of tumorigenesis associated with cancer metabolism, and yield strategies that exploit cancer metabolism for cancer therapy.