Loss of PHGDH in breast cancer triggers metastasis formation via glycome modulation

Metastasis formation is the leading cause of death in breast cancer patients and 30% of them will develop metastases. Mechanisms that lead to metastasis are poorly understood and we cannot predict which patient will develop metastases.

The Fendt lab has discovered that heterogeneous protein expression of the metabolic enzyme phosphoglycerate dehydrogenase (PHGDH) in primary tumors of breast cancer patients predicts metastasis. They find that loss of PHGDH expression drives an epithelial-to-mesenchymal transition (EMT).

The resulting invasiveness of PHGDH-low cancer cells depends on sialic acid metabolism, which provides an important precursor for protein glycosylation. Thus, I hypothesize that loss of PHGDH promotes a pro-metastatic cellular state, by modulating the cellular glycome.

Specifically, in a three-year span, I will address the following: 1) How is the glycome modified upon loss of PHGDH? 2) Which of the glycoconjugates induce EMT? 3) Does targeting glycosylation, reduce the metastatic capacity of breast cancer cells?

To this end, I will apply integrative glycomics, glycoproteomics, transcriptomics and genetic engineering combined with functional assays in breast cancer cells, mouse models and patient samples. In conclusion, I will deliver a mechanism, by which aberrant glycosylation drives metastasis of breast cancer cells.

I expect that this gain in mechanistic understanding will allow in the long-term to better predict and target metastasis formation in patients.