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Mechanistic insight into the role of carbonic anhydrases in cancer-associated immunity (ref: RDF20/APP/GIELING)

  • Full or part time

    Prof A McDermott
  • Application Deadline
    Friday, January 24, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Carbonic anhydrases (CAs) are a family of enzymes involved in the pH regulation of metabolically active cells/tissues. Upregulation of the CAIX/XII isoforms is associated with hypoxic tumours and clinically linked with malignant progression, treatment resistance and poor prognosis. CAIX/XII has a central role in maintaining a slightly alkaline intracellular pH in cancer cells (pHi), as these cells rely on glycolytic metabolism, producing high levels of protons and lactate. CAIX/XII activity leads to acidification of the extracellular environment (pHe). The biological influences of the lowered pHe on the tumour-supporting cells and in particular on the immune cells, is not well known. Preclinical studies suggest a link between the extracellular matrix (ECM) acidification and a reduced tumour-immune cell interaction, facilitating tumour growth and metastasis. The objective of the proposed project is to study the CAIX/CAXII-dependent communication between cancer and immune cell. Communication between these cells either direct (cell-cell contact) or indirect (through the release of cytokines/chemokines/growth factors) will be studied in 2D (monolayer) and 3D (multicellular spheroids) cell cultures of a mixture of metastatic cancer cells and immune cells. CAIX/XII activity will be inhibited by silencing of CA9 and CA12 genes (shCA9/CA12- cells) or by targeting the CAIX/XII activity with isoform-specific small molecular CA inhibitors (e.g. ureido-type sulfamate and benzenesulfonamide inhibitors). Characteristic features of aggressive cancer cells will be validated in specific in vitro assays for cytotoxicity, proliferation, migration and invasion. Our study many contribute to a better understanding of determinates controlling the tumour-associated immune cells and enhance the response to immunotherapy. The supervisory team will consist of Dr Roben Gieling and Prof Alison McDermott, Northumbria University Newcastle

Eligibility and How to Apply:

Please note eligibility requirement:

• Academic excellence of the proposed student i.e. 2:1 (or equivalent GPA from non-UK universities [preference for 1st class honours]); or a Masters (preference for Merit or above); or APEL evidence of substantial practitioner achievement.
• Appropriate IELTS score, if required.
• Applicants cannot apply for this funding if currently engaged in Doctoral study at Northumbria or elsewhere.

For further details of how to apply, entry requirements and the application form, see
https://www.northumbria.ac.uk/research/postgraduate-research-degrees/how-to-apply/

Please note: Applications that do not include a research proposal of approximately 1,000 words (not a copy of the advert), or that do not include the advert reference (e.g. RDF20/…) will not be considered.

Deadline for applications: Friday 24 January 2020
Start Date: 1 October 2020

Northumbria University takes pride in, and values, the quality and diversity of our staff. We welcome applications from all members of the community. The University holds an Athena SWAN Bronze award in recognition of our commitment to improving employment practices for the advancement of gender equality.

Funding Notes

The studentship is available to Home/EU students with a full stipend, paid for three years at RCUK rates (for 2019/20, this is £15,009 pa) and full fees.

References

Bryant JL, Gieling RG, Meredith SL, Allen TJ, Walker L, Telfer BA, Supuran CT, Williams KJ, White A. Novel carbonic anhydrase IX-targeted therapy enhances the anti-tumour effects of cisplatin in small cell lung cancer. Int J Cancer. 2018 Jan 1;142(1):191-201.

Wilson CL, Jurk D, Fullard N, Banks P, Page A, Luli S, Elsharkawy AM, Gieling RG, Chakraborty JB, Fox C, Richardson C, Callaghan K, Blair GE, Fox N, Lagnado A, Passos JF, Moore AJ, Smith GR, Tiniakos DG, Mann J, Oakley F, Mann DA. NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma. Nat Commun. 2015 Apr 16;6:6818.

Gieling RG, Babur M, Mamnani L, Burrows N, Telfer BA, Carta F, Winum JY,Scozzafava A, Supuran CT, Williams KJ. Antimetastatic effect of sulfamate carbonic anhydrase IX inhibitors in breast carcinoma xenografts. J Med Chem. 2012 Jun 14;55(11):5591-600.

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