Descrizione del progetto
Il ruolo degli endosomi riciclanti nell’interazione del tumore con lo stroma
L’endocitosi dei recettori della superficie cellulare regola la via di segnalazione nel corso della differenziazione, della proliferazione e della migrazione delle cellule. Le cellule tumorali invasive accumulano endosomi riciclanti nelle protusioni, fornendo recettori per la matrice extracellulare, regolando le interazioni delle cellule tumorali con il microambiente e coordinando la polimerizzazione dell’actina tramite le GTPasi della famiglia di Rho. La famiglia delle GTPasi Rab11 è coinvolta nella determinazione dell’aggressività del carcinoma ovarico sieroso di alto grado (HGSOC, High-Grade Serous Ovarian Carcinoma). Il progetto EndoPos, finanziato dall’UE, intende stabilire il posizionamento degli endosomi riciclanti all’interno delle cellule HGSOC che invadono la matrice extracellulare. Una combinazione di approcci innovativi aiuterà a chiarire il modo in cui il trasporto endocitico localizzato controlla le interazioni tumore-stroma e contribuisce alla progressione dell’HGSOC.
Obiettivo
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.
Campo scientifico
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Meccanismo di finanziamento
MSCA-IF-EF-ST - Standard EFCoordinatore
M13 9PL Manchester
Regno Unito