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


   Faculty of Biology, Medicine and Health


Manchester United Kingdom Cancer Biology Cell Biology Pharmacology

About the Project

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.

Our previous studies: Cancer cell metabolism and cytosolic Ca2+—Cancer cells undergo a switch from mitochondrial metabolism towards glycolysis which facilitates numerous cancer hallmarks, including cell proliferation, cell migration/invasion and resistance to cell death.. Although much less energy efficient, upregulation of glycolysis facilitates the accumulation of biosynthetic intermediates important for cell cycle progression and cell proliferation. Nevertheless, the production of ATP remains essential and is critical for fuelling the ATP-driven plasma membrane calcium pump (PMCA), which maintains low resting cytosolic Ca2+ and prevents cell death. Cutting off this glycolytic ATP supply to the PMCA causes cytotoxic Ca2+ overload and cell death [1-5].

PKM2 and the cell cycle—Pyruvate kinase-M2 (PKM2) is the major ATP-generating oncogenic glycolytic enzyme that fuels the PMCA. Our previous studies show that inhibition of PKM2 inhibits PDAC cell proliferation, migration and inhibits the PMCA leading to cytotoxic Ca2+ overload and cell death. However, a significant proportion of cells are resistant, due to heterogeneity of cells going through the cell cycle. This is because PKM2 can switch between low activity dimer, important for biosynthesis during G1/S phase, or high activity tetramer important for ATP production during G2/M phase required for cell division.

Hypothesis: We postulate that during G2/M tetrameric PKM2 predominates in PDAC cells, making them highly sensitive to PKM2 inhibitors, whereas during G1/S dimeric PKM2 predominates making them insensitive to PKM2 inhibitors

Aims and Objectives

We aim to develop strategies for arresting or synchronizing cells at G2/M (vs G1/S) of the cell cycle, which we hypothesize will sensitize PDAC cells to PKM2 inhibitor-induced cell death.

Impact: The successful outcome of this project will lead to the translation of a combination therapy to treat PDAC using cell cycle inhibitors followed by PKM2 inhibitors. Such combination therapies may be effective in other cancers where the PMCA is the major route of Ca2+ efflux, such as colorectal, breast, prostate, and lung, which tend to be the most aggressive and difficult to treat.

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

Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.

How to Apply

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select the appropriate subject area.

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.

Equality, Diversity and Inclusion 

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/ 


Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website).

References

1. James AD, Chan A, Erice O, Siriwardena AK, Bruce JIE. (2013) Glycolytic ATP fuels the plasma membrane calcium pump critical for pancreatic cancer cell survival. J Biol Chem. 288(50):36007-19
2. James AD, Patel W, Butt Z, Adiamah M, Dakhel R, Latif A, Uggenti C, Swanton E, Imamura H, Siriwardena AK, Bruce JIE. (2015) The Plasma Membrane Ca2+ Pump in Pancreatic Cancer Cells Exhibiting the Warburg Effect Relies on Glycolytic ATP. J Biol Chem. 290 (41) :24760-71.
3. James AD, Richardson D, Oh I-W, Sritangos P, Sultan A, Telfer B, Williams, K, Siriwardena AK, Bruce JIE. (2019). Cutting off the fuel supply to calcium pumps in pancreatic cancer cells: Role of pyruvate kinase-M2. Br J Cancer. 122(2): 266-278.
4. Richardson DA, Sritangos P, James AD, Sultan A, Bruce JIE. (2020). Metabolic regulation of calcium pumps in pancreatic cancer: role of phosphofructokinase-fructose-bisphosphatase-3 (PFKFB3). Cancer Metab.; 8:2.
5. Sritangos P, Pena Alarcon E, James AD, Sultan A, Richardson DA, Bruce JIE. (2020) Plasma Membrane Ca2+ ATPase Isoform 4 (PMCA4) has an important role in numerous hallmarks of pancreatic cancer. Cancers (Basel); 12(1):
Other relevant reviews:
6. Bruce JIE, James AD. (2020). Targeting the Calcium Signalling Machinery in Cancer. Cancers (Basel); 12(9):
7. Vander Heiden MG, Cantley LC, Thompson CB. (2009) Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation. Science 324(5930):1029-33
8. Cairns RA, Harris IS, Mak TW. (2011). Regulation of cancer cell metabolism. Nat Rev Cancer 11(2):85-9

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