Description du projet
Le métabolisme du pyruvate et le remodelage des matrices extracellulaires dans le ciblage du cancer métastatique
Les métastases, ou tumeurs secondaires, sont la principale cause de décès par cancer. De nombreuses patientes atteintes d’un cancer du sein obtiennent le diagnostic alors que les cellules cancéreuses se sont déjà disséminées dans les organes distants. Le remodelage des matrices extracellulaires (MEC) dans la niche métastatique est essentiel pour que les cellules disséminées du cancer du sein favorisent la croissance de la nouvelle métastase. Le laboratoire hôte a récemment découvert que le pyruvate, un nutriment, incite métaboliquement les cellules de cancer du sein à remodeler la MEC. Le projet MetaTarGet, financé par l’UE, capitalise sur cette découverte afin d’étudier le ciblage potentiel du remodelage de la MEC dans les métastases. La recherche se concentrera sur le métabolisme du pyruvate en tant que régulateur du remodelage de la MEC et sur une nouvelle stratégie thérapeutique pour cibler la croissance métastatique.
Objectif
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.
Champ scientifique
Programme(s)
Régime de financement
MSCA-IF-EF-ST - Standard EFCoordinateur
9052 ZWIJNAARDE - GENT
Belgique