It has recently become evident that cancer cells rewire their metabolism to meet their demands of proliferation and survival. Metabolic changes are dictated in part by the tumor nutrient environment as cancer cells are frequently starved for nutrients and exposed to toxic waste products due to a combination of increased nutrient consumption and dysfunctional vasculature. While the components of most metabolic pathways have long been described, it remains poorly understood how the flow of metabolites is rewired in the nutrient environment of tumors. I have recently developed two technologies to enable study of cancer cells in a tumor-like nutrient environment: a continuous flow cell culture system for maintaining reduced but steady nutrient concentrations (nutrostat) and a DNA-barcoded cell competition assay for simultaneously measuring the growth of pooled cancer cell lines cultured in the nutrostats. Focused on low glucose, these technologies enabled us to systematically investigate the cancer metabolic dependencies and discovered that most cancer cells reversibly switch to a more oxidative metabolism under low glucose conditions. However, a subset of cancers cells with heteroplasmic loss-of-function mtDNA mutations are unable to increase their oxygen consumption in low glucose conditions. This inability to induce oxidative metabolism hampers cell growth in the glucose-poor tumor environment and suggests the existence of a stronger positive selection for persistence of such mtDNA mutations. Supporting this notion, the prevalence of truncating mutations in mtDNA-encoded OXPHOS components is reported to be as high as 65%. It is, however, unclear why such a high percentage of cancer cells accumulate mtDNA mutations and how these mutations can be exploited as a liability for designing therapies. In this proposal, building on my previous observations, I aim to test the hypothesis whether heteroplasmic mtDNA mutations have functionally critical roles in tumorigenesis (Aim1) and confer metabolic liabilities that can be exploited for therapy (Aim2). Additionally, existence of metabolic vulnerabilities of cancer cells to low glucose calls for a more comprehensive examination of other nutrient dependencies. Therefore, as an extension to these aims, I will map the cancer nutrient dependencies using our DNA-barcoded cell competition assay (Aim3).
Cancer cells rewire their metabolism to meet their demands of proliferation and survival. This metabolic rewiring is partly dictated by the tumor nutrient environment as cancer cells are frequently starved for nutrients and exposed to toxic waste products due to a combination of increased nutrient consumption and dysfunctional vasculature. However, it remains poorly understood how the flow of metabolites is rewired in the nutrient environment of tumors. To begin to address this question, I will study the impact of mtDNA mutations on tumor metabolism and growth and map nutrient-dependent liabilities of cancer cells to exploit for cancer therapy.
|Garcia-Bermudez, Javier; Baudrier, Lou; La, Konnor et al. (2018) Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours. Nat Cell Biol 20:775-781|
|Minton, Denise R; Nam, Minwoo; McLaughlin, Daniel J et al. (2018) Serine Catabolism by SHMT2 Is Required for Proper Mitochondrial Translation Initiation and Maintenance of Formylmethionyl-tRNAs. Mol Cell 69:610-621.e5|
|Reczek, Colleen R; Birsoy, K?vanç; Kong, Hyewon et al. (2017) A CRISPR screen identifies a pathway required for paraquat-induced cell death. Nat Chem Biol 13:1274-1279|
|Alvarez, Samantha W; Sviderskiy, Vladislav O; Terzi, Erdem M et al. (2017) NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature 551:639-643|
|Ilic, Nina; Birsoy, K?vanç; Aguirre, Andrew J et al. (2017) PIK3CA mutant tumors depend on oxoglutarate dehydrogenase. Proc Natl Acad Sci U S A 114:E3434-E3443|
|Chen, Walter W; Freinkman, Elizaveta; Wang, Tim et al. (2016) Absolute Quantification of Matrix Metabolites Reveals the Dynamics of Mitochondrial Metabolism. Cell 166:1324-1337.e11|
|Pacold, Michael E; Brimacombe, Kyle R; Chan, Sze Ham et al. (2016) A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nat Chem Biol 12:452-8|