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What is the significance of MCT1 distribution to a novel subcellular location (nucleus) for cancer progression?


Project Description

MCT1 is a transmembrane protein involved in cell metabolism and mediates transport of monocarboxylates (such as pyruvate {a metabolic substrate} and lactate {a metabolic by product}) in and out of the cell. Increased plasma membrane (PM) expression of MCT1 has been reported in several cancer types including endometrial cancer and is associated with worse prognosis, reduced recurrence free and overall survival (1-3). Although the nucleus is not a usual location for monocarboxylate transporters (based on current knowledge on their function), we and others reported nuclear MCT1 (nMCT1) expression in endometrial (4) and soft sarcoma (5) biopsies. Both studies showed that patients with nMCT1 have a longer overall survival than the patients without it. In other words, MCT1 is protective when in the nucleus but harmful on the PM.

This four year PhD project aims to characterise and understand the biological significance of MCT1 subcellular localisation for cancer cell metabolism, progression and treatment outcome. To achieve this, endometrial cancer cell lines with MCT1 knock-down or with only nMCT1 or PM MCT1 expression will be engineered using CRISPR-CAS9 technology and will be subjected to functional assays measuring metabolic activity (MTT, Seahorse), proliferation (SRB, ki67, cell cycle analysis) and progression (migration/invasion). Further, the engineered cell lines will be characterised for their sensitivity to different chemotherapeutic agents and will be used to understand the impact of MCT1 subcellular localisation on treatment and patient outcome. Also, the potential of these chemotherapeutic agents on MCT1 expression or translocation will be evaluated. Additionally, the role of nMCT1 will be further characterised by identifying binding partners of nMCT1 using co-immunoprecipitation and by identifying alterations in gene expression in engineered cell lines. Information gathered from these experiments may identify novel targets that influence and/or are influenced by MCT1 subcellular localisation which may prove useful in cancer therapy.

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 a master’s degree in a related area/subject, and experience in molecular biology and/or gene editing (CRISPR) are encouraged to apply. Informal enquiries may be made directly to the primary supervisor. On the online application form select PhD Molecular Biology or Cancer Sciences.

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 2 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. Pinherio et al., 2010. Monocarboxylate transporter 1 is up-regulated in basal-like breast carcinoma. Histopathology. 2010;56:860–7.
2. deOliveira et al., 2012. Co-expression of monocarboxylate transporter 1 (MCT1) and its chaperone (CD147) is associated with low survival in patients with gastrointestinal stromal tumors (GISTs). J Bioenerg Biomembr. 2012;44:171–8.
3. Eilertsen et al., 2014. Monocarboxylate transporters 1-4 in NSCLC: MCT1 is an independent prognostic marker for survival. PLoS One. 2014;9:e105038.
4. Latif et al., 2017. Monocarboxylate Transporter 1 (MCT1) is an independent prognostic biomarker in endometrial cancer. BMC Clinical Pathology (2017) 17:27
5. Pinherio et al., 2014. Characterization of monocarboxylate transporters (MCTs) expression in soft tissue sarcomas: distinct prognostic impact of MCT1 subcellular localization. J Transl Med. 2014;12:118.

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