EndoPos · Endosome positioning in tumour-stroma interactions
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-05-01 → 2021-06-28
- EU contribution
- €224,934
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Endosome positioning in tumour-stroma interactions
More than 150,000 women die each year from ovarian cancer. Rab11 GTPase family (Rab11a/b/c) is implicated in determining the aggressiveness of ovarian cancer by delivering signalling molecules and receptors for extracellular matrix by recycling endosomes where cancer cells need them. The mechanism how is poorly understood and there is very limited option how to study the specific and redundant functions of individual members of Rab11 family. Furthermore, manipulating endosomal trafficking and signalling pathways with subcellular specificity is a challenge to cell biology. In the project EndoPos we use state-of-the-art innovative approaches to determine recycling endosomes positioning in ovarian cancer cells. First by BioID-based proteomics (a proximity labelling approach), second by developing a magnetogenetic approach to reposition endosomes in live ovarian cancer cells invading the extracellular matrix using external magnetic gradient. Finally, we use state of the art microscopy techniques for imaging Rab11s by exploiting CRISPR-Cas9 mediated knock-ins of ovarian cancer cells.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- THE UNIVERSITY OF MANCHESTER · ManchesterCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union