Programming Tumour Progression – Characterising the Role of the Endolysosomal System in Regulating Intracellular and Intercellular Signals
Supervisor: Dr Deborah Goberdhan, Professor Adrian Harris and Dr Clive Wilson
Applicants are invited to apply for a DPhil position focused on investigating the functions of the endolysosomal system in regulating tumour progression. Our recent work has highlighted the late endosomes and lysosomes (LELs) as a key nutrient-rich hub that can be hijacked by cancer cells to promote tumour growth and progression particularly under adverse conditions1. Cancers grow even under severe environmental stress, such as the hypoxic and low nutrient conditions caused by poor blood supply. The differential metabolic adaptations required to do this are currently an intense area of research, since they may provide new targets for therapy. Amino acid levels within the luminal compartments of the LELs drive cell growth in cancer by recruiting and activating mTORC1, a key nutrient-sensitive kinase, under normal and stress conditions. We have shown that this process requires members of the Proton-Assisted Amino Acid Transporter (PAT/SLC36) family on the surface of the LELs, highlighting them as potential anti-cancer targets2,3. Late endosomes are also involved in generating membrane-bound secreted vesicles called exosomes that are proposed to signal to other cells4 and prime new niches in which metastatic cancer cells can develop. We are studying how these two complementary processes of growth and exosome production are co-ordinately regulated in cancer cells. The project will involve a wide variety of genetic and biochemical approaches in a range of model systems. The student will be able to take advantage of a unique collaboration between research groups with complementary research strengths to pursue their particular research interests. Dr Goberdhan is a basic scientist with particular interested in cellular nutrient sensing using Drosophila and human cell culture1-3, Dr Wilson is a Drosophila developmental and reproductive biologist and Prof Harris is a clinical scientist, with a long term interest in the role of hypoxia and microenvironmental stresses in tumour development, who has considerable expertise in various cancer models and their clinical applications4,5. The student will be trained in a wide range of experimental approaches relevant to all these areas e.g., molecular biology, biochemical analysis, confocal imaging, human cell culture, fly genetics, in vivo mouse xenograft models. The ultimate aim of these studies is to develop new strategies to selectively target the growth and metastasis of cancer cells. Please contact Dr Goberdhan if you would like further details. Opportunities for funding through Oxford scholarship programmes are available to high calibre applicants who it is hoped will be attracted to this exciting and unique position.
Funding: Applicants are expected to compete for local studentships
Contact details: Deborah Goberdhan
Applications by: 4th January 2013 https://apply.embark.com/grad/Oxford/16/
Goberdhan, DCI (2010) Intracellular amino acid sensing and mTORC1-regulated growth: New ways to block an old target? COID 11, 1360-7. 2Heublein, S, Kazi, S, Ogmundsdóttir, MH, Attwood, EV, Kala, S, Boyd, CA, Wilson, C, Goberdhan, DCI (2010) Proton-assisted amino-acid transporters are conserved regulators of proliferation and amino-acid-dependent mTORC1 activation. Oncogene 29, 4068-79.
3Ögmundsdóttir MH, Heublein S, Kazi S, Reynolds B, Visvalingam SM, Shaw MK, Goberdhan DC (2012) Proton-assisted amino acid transporter PAT1 complexes with Rag GTPases and activates TORC1 on late endosomal and lysosomal membranes. PLoS One 7, e36616. 4McIntyre A, Patiar S, Wigfield S, Li JL, Ledaki I, Turley H, Leek R, Snell C, Gatter K, Sly WS, Vaughan-Jones RD, Swietach P, Harris AL (2012) Carbonic anhydrase IX promotes tumor growth and necrosis in vivo and inhibition enhances anti-VEGF therapy. Clin Cancer Res 18, 3100
11. 5Sheldon H, Heikamp E, Turley H, Dragovic R, Thomas P, Oon CE, Leek R, Edelmann M, Kessler B, Sainson RC, Sargent I, Li JL, Harris AL (2010) New mechanism for Notch signaling to endothelium at a distance by Delta-like 4 incorporation into exosomes. Blood 116, 2385-94.