Description:

The Department of Biochemistry and Molecular Genetics presents:

Jonathan Coloff, Assistant Professor, Physiology & Biophysics, University of Illinois, Chicago

Title: "Targeting Serine Auxotrophy in Luminal Breast Cancer"

Abstract:

A major challenge of targeting metabolism for cancer therapy is pathway redundancy, where multiple sources of critical nutrients can diminish the effects of metabolic therapies. An example of this can be found in recent attempts to target the serine synthesis pathway for cancer therapy, where the abundance of serine available to be taken up from the circulation has hampered the success of inhibitors of serine biosynthesis. This places a premium on pursuing strategies of limiting pathway redundancy if we wish to successfully target serine and other critical metabolic pathways for cancer therapy. We have taken the approach of analyzing human tumor gene expression data to identify scenarios where pathway redundancy is limited due to lineage-dependent gene expression, thereby creating potential vulnerabilities. Using this approach, we have found that the two major lineages of breast tumors—luminal and basal—express vastly different levels of PSAT1 (phosphoserine aminotransferase 1), the gene encoding the second enzyme of the serine synthesis pathway. Luminal breast cancer cells, which express extremely low levels of PSAT1, are unable to activate the serine synthesis pathway even when extracellular serine is completely absent. As a result, they are entirely dependent on exogenous serine for proliferation and survival and are sensitive to dietary serine and glycine starvation. This is in contrast to basal breast cancer cells, which are able to synthesize serine and proliferate in the absence of extracellular serine. Mechanistically, this serine auxotrophy is due to lineage-specific methylation of the PSAT1 gene in luminal breast tumors. Interestingly, the PSAT1 methylation and expression phenotypes observed in human breast tumors pre-exist in the cells-of-origin for these tumors in the normal mammary gland, emphasizing the importance of cell lineage in dictating this phenotype. Ongoing work in the Coloff Lab is continuing to characterize serine auxotrophy as a potentially targetable vulnerability of luminal breast tumors.