Dr H Laman, Dr S Turner
No more applications being accepted
Competition Funded PhD Project (Students Worldwide)
About the Project
This PhD position in the Paediatric Cancer Programme provides a unique opportunity for a highly motivated individual to conduct research within established labs investigating mechanisms of cell cycle control in cancer. The student will gain skills and expertise in the areas of cell biology and biochemistry, and in the fields of cell cycle regulation, T cell biology, and in vivo models.
Project Description
The deregulation of the G1/S phase transition occurs regularly in multiple cancer subtypes, including T cell malignancies (1). This can happen as a result of direct mutations, including inactivation of tumour suppressor genes, like the INK4 family members of cyclin dependent kinase (Cdk) inhibitors, CDKN2a and CDKN2b, the retinoblastoma gene RB1, and/or the overexpression of the proto-oncogenic subunits of the G1 phase kinase, Cdk6 and cyclins D2 and D3. Interestingly, cyclin D3 and Cdk6 are also absolutely required for tumours arising from the aberrant activation of other oncogenic signalling pathways, making the fidelity and function of this pathway critical for cancers, even if so-called ‘driver’ mutations do not occur in its core components. For example, mice lacking Cdk6 are resistant to thymic lymphoma caused by constitutively active Akt signalling, whereas mice lacking cyclin D3 are also fully resistant to the aggressive thymic lymphoma resulting from activated Notch signalling (2;3). The G1 cell cycle pathway and its core machinery therefore represent important potential therapeutic targets, and understanding how the disruption of this circuitry aids tumour development and how this can be prevented is important.
Our laboratory has discovered the F-box protein, Fbxo7, has non-SCF-dependent activity, acting as a cell cycle regulator that directly stabilises p27 and Cdk6, enhancing its activation by D-type cyclins (4). Fbxo7 has oncogenic activity as its over-expression in p53 null haematopoietic stem and progenitor cells (HSPCs) causes T-cell lymphoma in vivo (5). More recently, we have found that the loss of Fbxo7 expression revealed it has opposing roles on cell proliferation within the T cell lineage at different developmental stages. Paradoxically, it promotes proliferation of thymocytes within the thymus, but restrained proliferation of activated T cells in the periphery. This contradictory activity of Fbxo7 indicates that the G1 phase circuitry during T cell development is differentially regulated from that of mature T cells. This sets up the possibility that Fbxo7 may be required for T-cell malignancies deriving from immature thymocytes, but may act as a tumour suppressor gene in malignancies deriving from peripheral T cells. This PhD project sets out to test this idea directly using cultured cell lines of a number of immature (e.g. T lymphoblastic lymphoma/leukaemia) and mature T cell malignancies (e.g. Anaplastic Large Cell Lymphoma; ALCL) to determine whether Fbxo7 regulates the cell cycle differentially in these different tumour types and whether it can promote or suppress oncogenicity depending on the stage of T cell maturation, using inducible expression and knock-out systems. Depending on our findings, we will use a Nucleophosmin-Anaplastic Lymphoma Kinase (NPM-ALK)-driven mouse model of T cell malignancy that can be engineered to arise in the thymus or the periphery (6) to test the tumour-suppressive or tumour-promoting effect of Fbxo7 on tumours arising in different niche environments. The student will gain skills and expertise in the areas of cell biology and biochemistry, and in the fields of cell cycle regulation, T cell biology, and in vivo models.
Funding Notes
This is one of 20 projects being advertised by the Cambridge Cancer Centre, a partnership between the University of Cambridge, Cancer Research UK and Cambridge University Hospitals NHS Foundation Trust bringing together academic researchers, clinicians, and industry collaborators in the Cambridge area. Up to 10 awards (supporting both clinical and non-clinical students) will be available. Non-clinical studentships fund the University Composition Fee (Home/EU rate), provide a consumables budget, and a stipend, currently £19,000 per annum. Clinical research fellowships cover salary costs for the fellow, a consumables budget, and funding for the University Composition Fee (at staff rate) for three years.
References
(1) Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144(5):646-674.
(2) Hu MG, Deshpande A, Enos M, Mao D, Hinds EA, Hu GF et al. A requirement for cyclin-dependent kinase 6 in thymocyte development and tumorigenesis. Cancer Res 2009; 69(3):810-818.
(3) Sicinska E, Aifantis I, Le Cam L, Swat W, Borowski C, Yu Q et al. Requirement for cyclin D3 in lymphocyte development and T cell leukemias. Cancer Cell 2003; 4(6):451-461.
(4) Nelson DE, Randle SJ, Laman H. Beyond ubiquitination: the atypical functions of Fbxo7 and other F-box proteins. Open Biol 2013; 3(10):130131.
(5) Lomonosov M, Meziane eK, Ye H, Nelson DE, Randle SJ, Laman H. Expression of Fbxo7 in haematopoietic progenitor cells cooperates with p53 loss to promote lymphomagenesis. PLoS One 2011; 6(6):e21165.
(6) Malcolm TI, Villarese P, Fairbairn CJ, Lamant L, Trinquand A, Hook CE et al. Anaplastic large cell lymphoma arises in thymocytes and requires transient TCR expression for thymic egress. Nat Commun 2016; 7:10087.