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Cutting off the fuel supply to calcium pumps in pancreatic cancer: a novel therapeutic strategy


Project Description

Background and Rationale: Pancreatic ductal adenocarcinoma (PDAC) has the poorest survival and limited treatment options. Therefore, the search for novel therapeutic targets and drugs designed to selectively kill PDAC cells must remain a central research strategy.
Cancer cell metabolism and cytosolic Ca2+—PDAC cells undergo a switch from mitochondrial to glycolytic metabolism (Warburg effect) which facilitates numerous cancer hallmarks, including cell proliferation, cell migration/invasion and resistance to cell death. Our previous and pilot studies show that this increased glycolytic ATP is also important for fuelling the plasma membrane calcium pump (PMCA), as cutting off this glycolytic ATP supply to the PMCA causes cytotoxic Ca2+ overload and cell death[1, 2]. This therefore represents a novel therapeutic strategy for the treatment of PDAC. Pilot studies show that the oncogenic glycolytic enzymes (GEs) pyruvate kinase-M2 (PKM2), phosphofructokinase fructose bisphosphatase-3 (PFKFB3) and the rate-limiting phosphofructokinase-1 (PFK1), all associate with the plasma membrane, potentially providing a privileged ATP supply to the PMCA.
Hypothesis: The functional coupling of glycolytic enzymes with the PMCA represents a critical cancer-specific phenotype of PDAC cells. Disrupting this functional coupling may represent a novel therapeutic strategy for selectively killing PDAC cells while sparing non-cancer cells.
Aims and Objectives
1-Identify membrane glycolytic enzyme-binding proteins that functionally couple glycolytic enzyme with the PMCA.
2-Investigate the effects of altered expression of key oncogenic glycolytic enzymes and putative binding proteins in PDAC cell lines and on PDAC tumour growth and tumour cell injury in vivo.
Impact: The successful outcome of this project will pave the way for identifying novel therapeutic targets for the treatment of pancreatic cancer. Such drugs may be effective in other cancers where the PMCA is the major route of Ca2+ efflux, such as colorectal, breast, prostate, and stomach, which tend to be some of the most aggressive and difficult to treat.

Training/techniques to be provided:
We have assembled a supervisory team with diverse but complimentary technical and clinical expertise that will provide a multidisciplinary training environment for the student.
Co-Supervisors:
Dr Jason Bruce (FBMH) will provide training in all aspects of acute cell isolation, tissue histology, protein biochemistry and fluorescence imaging to assess multiple readouts of pancreatic acinar cell/tissue injury.
Prof Kaye Williams will provide essential training in in vivo techniques such as xenograft models of cancer and intravital microscopy of tumour cells in vivo. Prof Williams also holds the Home Office project license for all in vivo studies.
Dr Andrew Gilmore will provide training in molecular biology techniques such as molecular cloning, creating stable cell lines using lentiviral expression systems and doxycycline-induced gene deletion systems and the newly developed BioID techniques for identifying protein-protein interactions.

Entry Requirements:
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. Candidates with extensive technical experience relevant to the current project, either during an extended laboratory project, either during their Bachelor’s or Masters’ Degree are encouraged to apply. Relevant techniques include, but are not limited to:
• mammalian cell culture, tissue dissection and primary cell isolation
• tissue histology, immunocytochemistry
• conventional and fluorescence microscopy
• protein biochemistry: immunoblotting, ELISA, immunoprecipitation, phosphorylation assays
• molecular techniques: DNA/RNA extraction, PCR, recombinant protein expression and cloning
• in vivo techniques; husbandry, breeding and genotyping

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1. James, A., et al., (2013) J Biol Chem, 288 (50): 36007-19.
2. James, A., et al., (2015) J Biol Chem, 290(41): 24760-71.
3. Roux, K.J., et al., (2012) J Cell Biol, 196(6): 801-10.
Other relevant papers:
4. Vander Heiden MG, Cantley LC, Thompson CB. (2009) Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation. Science 324(5930):1029-33
5. Cairns RA, Harris IS, Mak TW. (2011). Regulation of cancer cell metabolism. Nat Rev Cancer 11(2):85-95.

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