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Targeting metabolic regulation in metastasis formation

Project description

Pyruvate metabolism and extracellular matrix remodelling in the targeting of metastatic cancer

Metastases, or secondary tumours, are the leading cause of cancer deaths. Many breast cancer patients get the diagnosis when cancer cells have already disseminated to distant organs. Extracellular matrix (ECM) remodelling in the metastatic niche is essential for disseminated breast cancer cells to promote the growth of the new metastasis. The host laboratory has recently discovered that the nutrient pyruvate metabolically drives breast cancer cells to remodel the ECM. The EU-funded MetaTarGet project is capitalising on this discovery to explore the potential targeting of ECM remodelling in metastasis. The research will focus on pyruvate metabolism as an ECM remodelling regulator and a novel therapeutic strategy to target metastatic outgrowth.

Objective

Distant metastases, i.e. secondary tumors, are the leading cause of cancer deaths. Many patients (especially with breast cancer) are diagnosed when cancer cells have already disseminated to distant organs. Thus, it is of profound importance to prevent the metastatic outgrowth of these disseminated cancer cells into secondary tumors. The ability to remodel the extracellular matrix (ECM) of the metastatic niche is essential for disseminated breast cancer cells to promote their own metastatic outgrowth. This process is to date believed to be transcriptionally regulated. However, the Fendt laboratory has discovered that the nutrient pyruvate metabolically drives ECM remodeling by breast cancer cells. In my project, I will build on this discovery and explore how to target ECM remodeling in metastatic outgrowth. First, I will determine the interaction between the discovered metabolic and the known transcriptional regulation of ECM remodeling. Secondly, I will translate this novel finding into therapeutic potential by defining how to selectively target it, thereby impairing metastatic outgrowth in the lung environment. Thirdly, I will define how the metastatic site and the cancer cell origin affect the discovered metabolic regulation of ECM remodeling, and thus metastatic outgrowth. To address these aims, I will use metabolomics, 13C tracer analysis, genetic engineering and nanotechnology-based drug-delivery in breast cancer 3D cultures and mouse models. With MetaTarGet, I will deliver (i) a mechanistic understanding of pyruvate metabolism as a regulator of ECM remodeling, and (ii) a novel therapeutic strategy to target metastatic outgrowth. This project will allow me to bridge my nanotechnology-based drug-delivery knowledge with the expertise of the Fendt laboratory in metastasis metabolism. Consequently, I will strengthen my research competences and enhance my personal research profile.

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Coordinator

VIB VZW
Net EU contribution
€ 166 320,00
Address
Rijvisschestraat 120
9052 Zwijnaarde - gent
Belgium

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Region
Vlaams Gewest Prov. Oost-Vlaanderen Arr. Gent
Activity type
Research Organisations
Links
Other funding
€ 0,00