Descripción del proyecto
El metabolismo del piruvato y la remodelación de la matriz extracelular para combatir el cáncer metastásico
Las metástasis, o tumores secundarios, son la principal causa de las muertes por cáncer. Muchos pacientes con cáncer de mama son diagnosticados cuando las células cancerosas ya se han diseminado hasta órganos distantes. La remodelación de la matriz extracelular (MEC) en nichos metastásicos es fundamental para que las células del cáncer de mama fomenten el crecimiento de nuevas metástasis. El laboratorio anfitrión ha descubierto recientemente que el nutriente piruvato activa metabólicamente las células cancerosas para que remodelen la MEC. El proyecto MetaTarGet, financiado con fondos europeos, aprovecha este descubrimiento para estudiar el potencial de actuar sobre la remodelación de la MEC en la metástasis. La investigación se centrará en el metabolismo del piruvato como regulador de la remodelación de la MEC y en una estrategia terapéutica novedosa para combatir el crecimiento metastásico.
Objetivo
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.
Ámbito científico
Programa(s)
Régimen de financiación
MSCA-IF-EF-ST - Standard EFCoordinador
9052 ZWIJNAARDE - GENT
Bélgica