Dr J Bruce
Prof K Williams
Dr C Jorgensen
Prof J W Valle
No more applications being accepted
Competition Funded PhD Project (Students Worldwide)
About the Project
Pancreatic adenocarcinoma (PDAC) is the most deadly cancer with poor prognosis and very limited treatment options. All cancer cells undergo a switch from mitochondrial metabolism towards glycolysis which facilitates numerous cancer hallmarks. Although much less energy efficient, this upregulation of glycolysis facilitates the accumulation of biosynthetic intermediates important for cell cycle progression and cell proliferation. Nevertheless, the production of ATP remains essential for the many energy consuming processes of a cancer cell, most notably the ATP-driven plasma membrane calcium pump (PMCA), which maintains low resting cytosolic Ca2+ and prevents cell death. Pyruvate kinase-M2 (PKM2) is the major ATP-generating oncogenic glycolytic enzyme responsible for fuelling the PMCA. Our previous studies show that inhibition of PKM2 (with shikonin) inhibits numerous PDAC cancer hallmarks (cell proliferation, migration) and cuts off the ATP supply to the PMCA leading to cytotoxic Ca2+ overload and cell death. However, not all cells die and 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 bioenergetics during G2/M phase and the ATP-demanding process of cell division. We postulate that the major source of ATP during G2/M in PDAC cells is tetrameric PKM2, making them highly sensitive to PKM2 inhibitors. During G1/S dimeric PKM2 diverts glucose metabolism to biosynthesis, and therefore mitochondrial metabolism of alternative substrates (glutamine) is necessary to maintain ATP. We aim to develop strategies for arresting or synchronizing cells at G2/M (vs G1/S) of the cell cycle, which we hypothesise will markedly sensitize PDAC cells to PKM2 inhibitors and thus induce energetic crisis and cell death. Such a strategy may be translated as a combination therapy to treat PDAC using cell cycle inhibitors followed by PKM2 inhibitors.
Candidates must hold, or be about to obtain, a minimum upper second class (or equivalent) undergraduate degree in a relevant subject. A related master’s degree would be an advantage.
UK applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).
If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.
Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.
To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the CRUK Manchester Centre PhD Training Scheme (MCRC) website https://www.bmh.manchester.ac.uk/study/research/funded-programmes/mcrc-training-scheme/
General enquiries can be directed to [Email Address Removed].
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/
Interview date – 8 January 2021
Funding will cover UK tuition fees/stipend only (currently at £19,000 per annum) and running expenses. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of bursaries that will enable a limited number of full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.
The duration of this project is four years to commence in October 2021.