(MCRC Non-Clinical) Investigation of the role of the small GTPase RAC1 in invasion and metastasis of Small Cell Lung Cancer
About the Project
Small cell lung cancer (SCLC) is an aggressive tumour, where 80% of patients have metastatic disease at diagnosis. Underlying this aggressiveness is intra-tumoural heterogeneity. Most SCLC tumours contain two different cell types, the majority being neuroendocrine (NE) with a small subset of non-neuroendocrine (non-NE). A phenotype switch from NE to non-NE generates the non-NE phenotype. Importantly, SCLC tumour heterogeneity is required for metastasis as co-operation between both cell types is needed.
The mechanistic understanding of NE to non-NE transition and its role in SCLC invasion and metastasis has been hindered by the lack of plasticity of established SCLC cell lines. However, we are fortunate to have access to patient circulating tumour cell-derived explant models which can undergo NE to non-NE transition. Using these, we have recently shown that the small GTPase RAC1 is highly active in non-NE cells and promotes NE to non-NE transition. RAC1 is a molecular switch, cycling between inactive GDP and active GTP-bound forms. Active RAC1 has established roles in stimulating migration/invasion of several cancer cells, but its role in migration/invasion and metastasis of SCLC is unknown.
Given the established roles of RAC1 in migration/invasion, its role in NE to non-NE transition and the requirement of both NE and non-NE cells for metastasis, this project aims to decipher the molecular and cellular mechanisms by which RAC1 signalling stimulates invasion and metastasis of SCLC both in vitro and in vivo. This project combines the expertise of the supervisory team in RAC1 signalling, matrix and SCLC biology with access to unique SCLC patient-derived models, presenting an unparalleled opportunity to uncover the mechanisms underpinning SCLC progression.
The supervisory environment is supportive and values inclusivity and diversity. The student will present their work internally and at scientific conferences and receive mentoring for successful career progression alongside valuable training in transferable skills.
Eligibility
You should also hold, or about to obtain, a minimum Upper Second Class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline. A related master’s degree would be an advantage.
International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English language) before contacting potential supervisors to express an interest in their project. Eligibility information can be found on the University's Country Specific information page.
Before you Apply
Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.
How to Apply
For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. On the online application form select MCRC PhD Programme.
Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application, please contact our admissions team.
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.
Applications Timeline
Applications open: 11 October 2024
Application deadline: 15 November 2024
Interviews: 17th January 2025
Start date: September 2025
Funding Notes
MCRC - CRUK Manchester Cancer Research Centre Studentship funding is for a duration of four years to commence in September 2025 and covers UK tuition fees and an annual stipend. Funding will cover UK tuition fees and stipend only.
International Candidates
We are able to offer a limited number of bursaries to high- performing EU and international candidates, covering PhD fees only. Bursaries do not include financial support for visa/health surcharges. We asses each EU and international candidate's suitability for a bursary at the application and interview stages.
References
2. Calbo J, van Montfort E, Proost N, van Drunen E, Beverloo HB, Meuwissen R, Berns A. A functional role for tumor cell heterogeneity in a mouse model of small cell lung cancer. Cancer Cell 19:244–256, 2011.
3. Simpson KL, Stoney R, Frese KK, Simms N, Rowe W, Pearce SP, Humphrey S, Booth L, Morgan D, Dynowski M, Trapani F, Catozzi A, Revill M, Helps T, Galvin M, Girard L, Nonaka D, Carter L, Krebs MG, Cook N, Carter M, Priest L, Kerr A, Gazdar AF, Blackhall F, Dive C. A biobank of small cell lung cancer CDX models elucidates inter- and intratumoral phenotypic heterogeneity. Nature Cancer 1: 437–451, 2020.
4. Payapilly A, Guilbert R, Descamps T, White G, Magee P, Zhou C, Kerr A, Simpson KL, Blackhall F, Dive C, Malliri A. TIAM1-RAC1 promote small-cell lung cancer cell survival through antagonizing Nur77-induced BCL2 conformational change. Cell Rep 37, 2021.
5. Mack NA, Whalley HJ, Castillo-Lluva S, Malliri A. The diverse roles of Rac signaling in tumorigenesis. Cell Cycle 10: 1571-81, 2011 (Review).
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