Descripción del proyecto
El papel de los endosomas de reciclaje en la interacción del tumor con el estroma
La endocitosis de los receptores de la superficie celular regula la señalización durante la diferenciación, la proliferación y la migración de las células. Las células cancerosas invasoras acumulan endosomas de reciclaje en sus protuberancias, lo que favorece el suministro de receptores para matriz extracelular que regula las interacciones de las células cancerosas con el microambiente, y coordina la polimerización de actina a través de las GTPasas de la familia Rho. La familia Rab11 de GTPasas está implicada en la determinación de la agresividad del carcinoma de ovario seroso de alto grado (COSAG). El objetivo del proyecto financiado con fondos europeos EndoPos es determinar la ubicación de los endosomas de reciclaje en las células del COSAG que invaden la matriz extracelular. La combinación de métodos innovadores ayudará a determinar la manera en la que el tráfico endocítico localizado controla las interacciones entre el tumor y el estroma y contribuye a la evolución del COSAG.
Objetivo
Endocytosis of cell surface receptors controls signaling during proliferation, differentiation and migration of cells, and plays a significant role in cancer progression. Invasive cancer cells accumulate recycling endosomes (including Rab11) at protrusions. This promotes the delivery of integrins, receptors for extracellular matrix, to regulate interactions between tumour cells and their surroundings, and coordinates actin polymerization through Rho family GTPases. The Rab11 family is particularly important in determining the aggressiveness of high-grade serous ovarian carcinoma (HGSOC). Despite its importance, the machinery that guides Rab11 trafficking and the functions of polarized trafficking are not clear in HGSOC. I aim to determine how recycling endosomes are positioned within HGSOC cells invading extracellular matrix, using BioID-based proteomics (a proximity labelling approach well established in the host lab) to identify the Rab11-associated machinery in HGSOC cells. I further aim to actively manipulate the dynamics of Rab11 positive endosomes in invading cells by developing a magnetogenetic approach to reposition endosomes in live cells, using a combination of my developed skills (including live imaging, protein engineering). Both cutting-edge methods will be applied in the most physiological and cancer relevant context to lend clinical relevance to our observations. Combining these innovative approaches will provide molecular detail and mechanistic insight to elucidate how localised endocytic trafficking controls tumour-stroma interactions in the metastatic niche and contributes to HGSOC lethality. This work will further provide targets for therapies aimed at suppressing metastasis and preventing relapse in HGSOC, a lethal form of ovarian cancer that has one of the worst survival rates (<40% 5-year survival). Moreover, this project will allow me to acquire technical skills and expertise essential for my development as an independent researcher.
Ámbito científico
Programa(s)
Régimen de financiación
MSCA-IF-EF-ST - Standard EFCoordinador
M13 9PL Manchester
Reino Unido