Person: German, Natalie Janelle
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German
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Natalie Janelle
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German, Natalie Janelle
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Publication Investigating and Exploiting Metabolic Vulnerabilities in Cancer(2015-04-21) German, Natalie Janelle; Michel, Thomas; Manning, Brendan; Vander Heiden, MatthewFuel metabolism in healthy cells is not sufficient to sustain the biosynthetic and energetic demands of cancer. For a normal cell to transform to a rapidly dividing tumor cell, metabolism must be dramatically altered in a process called metabolic reprogramming, characterized by increased nutrient uptake and re-purposing. As we move toward a future of personalized medicine, there is new opportunity in targeting the metabolic requirements specific to an individual’s tumor. To this end, it is critical to understand molecular drivers that cancer cells hijack to modify metabolism. In this dissertation, I describe three studies on enzymes and metabolic pathways that shed light on molecular regulation of metabolic reprogramming in cancer. First, we screened for substrates of SIRT4, a mitochondrial sirtuin that promotes metabolic homeostasis and suppresses cancer by mechanisms not well understood. We used proteomics to identify hyperacetylated mitochondrial proteins in SIRT4 knockout mouse tissues compared to wildtype. We find SIRT4 binds and inhibits pyruvate carboxylase, an enzyme important for refueling the TCA cycle in cancer, indicating SIRT4 may target this node in tumor metabolism. Second, we reveal a role for prolyl hyrdoxylase domain (PHD) 3 in coordinating cancer cell addition to fat catabolism. In biochemical and cellular studies, we find PHD3 hydroxylates and activates acetyl-CoA carboxylase (ACC2) to repress fatty acid oxidation (FAO). Loss of this regulatory axis in leukemia enables greater utilization of fatty acids as fuel, and also serves as a liability by rendering cells susceptible to FAO inhibition. Finally, we used metabolomics to define alterations caused by the diabetes drugs metformin and phenformin to better understand their anti-cancer properties. We analyzed the drugs’ effects on cells undergoing neoplastic transformation and on cancer stem cells (CSCs), a small population that possesses predominant tumor-initiation capacity and is selectively inhibited by metformin. We show metformin and phenformin induce changes that oppose cancer cell survival by eliciting a nutrient crisis during transformation and depleting nucleotide triphosphates in CSCs. In sum, these findings contribute to the future potential to impede nutrient switches in cancer, thus turning the metabolic dependencies of cancer cells into metabolic vulnerabilities.Publication SIRT4 controls the balance between lipid synthesis and catabolism by repressing malonyl-CoA decarboxylase(BioMed Central, 2012) Laurent, Gaëlle; German, Natalie Janelle; Saha, Asish K; de Boer, Vincent CJ; Fischer, Frank; Boanca, Gina; Dephoure, Noah Elias; Vaitheesvaran, Bhavapriya; Davies, Michael; Gygi, Steven; Muoio, Deborah M; Kurland, Irwin J; Steegborn, Clemens; Ruderman, Neil B; Haigis, Marcia