About the Project
Background. Because of tumour growth rate and limited blood supply, the tumour microenvironment is often hypoxic and deprived of nutrients (including glucose and amino acids). Therefore, cancer cells adopt a variety of strategies to obtain metabolic fuels, and the ‘use of opportunistic modes of nutrient acquisition’ is a hallmark of cancer metabolism. Recently, macropinocytosis, an endocytic pathway that allows bulk uptake of extracellular fluids and proteins, was shown to be a key source of nutrients for cancer cells. The Rainero lab has demonstrated that invasive cancer cells also macropinocytose and degrade extracellular matrix (ECM) components to sustain their growth under conditions of nutrient starvation. The Smythe lab recently identified new macropinocytosis regulators using a genome wide-siRNA screen of the kinome. Here, we aim to test whether these newly identified macropinocytosis regulators control ECM internalisation to modulate cancer cell growth and metabolism in vitro and in vivo.
Objectives. This project will characterise the role of macropinocytosis regulators in controlling:
1. ECM internalisation
2. Cancer cell growth and metabolism in vitro
3. Cancer growth and metastasis in vivo
Novelty. The role of ECM uptake and degradation in promoting cancer growth and metastasis is a newly emerging area. We have candidate regulators of macropinocytosis and a recently developed and genetically amenable Drosophila model of metastasis which will allow us to test the role of these regulators in cancer progression.
Timeliness. Recent evidence suggests that the inhibition of nutrient scavenging pathways, alone or in combination, could provide substantial benefit for patients with solid tumours. The outcomes of this study will thus significantly progress the cancer metabolism field, potentially leading to the identification of novel targets for therapeutic interventions.
Experimental approach. The Rainero lab has developed imaging-based approaches to visualise and quantify ECM internalisation, which will be used to assess the contribution of the identified macropinocytosis regulators in this process. Moreover, state-of-the-art high-content imaging and metabolomics, coupled with 3D culture systems, will be used to monitor cancer cell growth and metabolism. Mechanisms identified as important in objectives 1 and 2 will be tested in vivo in a Drosophila melanogaster model for metastatic Colorectal cancer.This exciting model was recently developed in the Campbell lab, and is highly amenable to genetic manipulation, high-throughput and high-resolution analyses, making it possible to assay for effects on distinct steps of the metastatic pathway.
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme and how to apply can be found on our website:
Studentships commence: 1st October 2021
Glutaminolysis drives membrane trafficking to promote invasiveness of breast cancer cells. Dornier E, Rabas N, Mitchell L, Novo D, Dhayade S, Marco S, Mackay G, Sumpton D, Pallares M, Nixon C, Blyth K, Macpherson IR, Rainero E, Norman JC. Nat Commun. 2017 Dec 21;8(1):2255. doi: 10.1038/s41467-017-02101-2.
Collective cell migration and metastases induced by an epithelial-to-mesenchymal transition in Drosophila intestinal tumors. Campbell K, Rossi F, Adams J, Pitsidianaki I, Barriga FM, Garcia-Gerique L, Batlle E, Casanova J, Casali A. Nat Commun. 2019 May 24;10(1):2311. doi: 10.1038/s41467-019-10269-y.
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