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The role of tumor microenvironment in promoting PHGDH loss-induced metastasis formation

Metastasis formation is the main cause of death in breast cancer (BC) patients. Our limited understanding of how cancer cells gain metastatic ability greatly reduces the chance to predict which patient will develop metastasis. The Fendt lab discovered that heterogeneity in the expression of the metabolic enzyme phosphoglycerate dehydrogenase (PHGDH) in primary tumors of BC patients is indicative of metastasis formation and that PHGDH loss drives metastatic ability in mouse models. However, it remains unknown what induces cancer cells to lose PHGDH and consequently to disseminate. My preliminary data indicate that cancer cells in highly vascularized areas of PDX BC tumors show low PHGDH protein expression. Thus, I hypothesized that in the tumor microenvironment the crosstalk between cancer cells and endothelial cells (EC) causes PHGDH loss. To address this hypothesis, I will investigate: 1) How do ECs induce the loss of PHGDH protein expression? 2) What is the communication signals between ECs and cancer cells resulting in the loss of PHGDH protein expression? 3) Does a crosstalk-specific gene signature predict metastasis risk in patients? I will use in vitro and in vivo models of BC metastasis, combined with intravital imaging, genetic engineering, RNA sequencing and patient data. I expect to identify the communication signal between cancer cells and ECs that drives PHGDH loss and metastatic dissemination, and to assess its ability to predict patients' metastatic risk.

Date:19 Apr 2021 →  Today
Keywords:SLC35A3, Glycoproteome, Metastasis organotropism
Disciplines:Cellular interactions and extracellular matrix, Medical biochemistry and metabolism not elsewhere classified, Posttranslational modifications, Intracellular compartments and transport, Cancer biology
Project type:PhD project