Ji Yeon Kim, PhD

Cancer is a disease of uncontrolled cell growth. As the disease advances, the cancer can leave the original site and spread to other parts of the body. The ability to grow and invade is energetically costly though. Thus, cancer cells will modify their metabolism to meet these high energy requirements. This includes aggressively using nutrients to produce more energy (ATP), making building blocks for growth (protein, plasma membranes, DNA) and finding ways to overcome metabolic stress (e.g., reactive oxygen species). In other words, if we can identify metabolic changes that occur only in cancer, then impacting the altered metabolic pathways could enable us to selectively kill cancer cells and not impact normal cells. We are interested in the metabolism of the sugar molecules fructose and mannose. We discovered that the balance between fructose and mannose is important when lung cancer becomes aggressive. Only these aggressive lung cancer cells were killed when the conversion of fructose to mannose was disrupted. During the report period, we found that disrupting balance between fructose and mannose block self-eating mechanism (autophagy) in cancer cells, leading to death. Furthermore, we revealed that inhibition of self-eating mechanism while blocking mannose metabolism can significantly reduce tumor volume in mice. If successful, this study will provide clues as to why disrupting balance between fructose and mannose (e.g., drinking soda (fructose) can increase cancer risk while consuming mannose slows tumor growth) is important for cancer therapy. Ultimately, we want to answer whether targeting this sugar pathway can help treat patients.
 

Update: We found that KRAS/LKB1 co-mutant cells also exhibit an increased dependence on N-acetylglucosamine-phosphate mutase 3 (PGM3), an enzyme downstream of GFPT2. Genetic or pharmacologic suppression of PGM3 reduced KRAS/LKB1 co-mutant tumor growth in both in vitro and in vivo settings. Our results define an additional metabolic vulnerability in KRAS/LKB1 co-mutant tumors to the HBP and provide a rationale for targeting PGM3 in this aggressive subtype of NSCLC. *Lee HM, Cai F, Kelekar N, Bellapuly and Kim J. Targeting PGM3 as a novel therapeutic strategy in KRAS/LKB1 co-mutant lung cancer. Cells. 2022;11(1). Epub 2022/01/12. doi: 10.3390/cells11010176. PubMed PMID: 35011738; PMCID: PMC8750012. *Lieu EL, Kelekar N, Bhalla P, Kim J. Fructose and Mannose in Inborn Errors of Metabolism and Cancer. Metabolites. 2021;11(8). Epub 2021/08/27. doi: 10.3390/metabo11080479. PubMed PMID: 34436420; PMCID: PMC8397987.