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Cancer Metabolism and Metabolic Toxicity

The collective metabolic network of a cell is extensive and versatile, allowing the cell to allocate resources such as glucose and amino acids along different metabolic routes to serve specific biological processes. In cancer, several examples are known where cells modify their metabolism to preferentially ‘fuel’ cancer specific processes such as unchecked growth and cellular transformation, and thus targeting these pathways may provide therapeutic benefit.

On the other hand, within the cellular metabolic network, some metabolites appear to be inherently toxic or toxic when allowed to accumulate to abnormal levels, with a selective window of toxicity towards certain cell types or organs which is poorly understood. This is demonstrated in many amino acid breakdown disorders; in the example of phenylketonuria, severe toxicity in the developing brain occurs from loss of phenylalanine hydroxylase, an enzyme involved in phenylalanine catabolism, resulting in a toxic buildup of phenylalanine and phenylalanine byproducts.

Along these lines, we found that glycine decarboxylase (GLDC), an enzyme lost in the glycine breakdown disorder nonketotic hyperglycinemia, is selectively essential in a subset of cancer cells. GLDC is only essential in cancer cells that highly express serine hydroxymethyltranferase 2 (SHMT2) and thus produce glycine in the mitochondria at an elevated rate. Loss of GLDC kills these cells by causing a toxic buildup of the glycine byproducts aminoacetone and methylglyoxal.

This demonstrates that some cancers elevate and utilize certain metabolic pathways which involve the formation and catabolism of toxic metabolites. By identifying these pathways and targeting the catabolic steps, we may uncover a novel class of targets that can be exploited to poison cancer cells with their own metabolites, as well as obtain insights into the roles of such pathways in physiology and disease.

Understanding the role of GCAT and glycine-to-aminoacetone conversion in physiology and in cancer

Modeling and characterizing the ischemic tumor metabolic environment

Investigating toxic metabolite pathways and metabolite detoxifying enzymes in cancer

It is increasingly appreciated that large scale metabolic changes accompany physiological and pathological changes in cell state, suggesting the possible involvement of toxic metabolic pathways in many processes outside of cancer. We are interested in collaborating with other groups to investigate the involvement of toxic metabolites in various pathological states such as neurodegenerative disorders and aging. We hope that our efforts in exploring toxic metabolite pathways will have far-reaching implications in better understanding cell metabolism and in treating various states of human disease.