The effect of oncogenic transformation on the environmental independence of cancer cell divisions
Supervisors: Prof Buzz Baum, Professor Tim Meyer and Dr Helen Matthews
Start date: September 2016
The capacity of tumour cells to metastasise is the dominant cause of death in cancer patients, yet the biology of metastasis remains poorly understood. To generate successful metastases cancer cells must acquire the ability to translocate, survive and complete cell division in biochemically and mechanically diverse environments very different to their tissue of origin. This ability is likely due in part to changes in the mitotic cortex, downstream of oncogenic transformation, which provides protection from external mechanical forces during mitosis. Mitotic rounding, the dramatic actin- dependent change in cell shape at mitosis, is emerging as a process that malignant cells may harness to overcome foreign and hostile environments that normally prohibit cell division1. The rigid actin cortex provides a protective space within which crucial aspects of mitosis such as spindle orientation and chromosome segregation. can occur undisturbed by external forces. Moreover, data from the Baum laboratory shows that cancer cells have an augmented rounding ability and are more dependent on mitotic rounding for efficient mitotic progression than their non-transformed counterparts
The Baum laboratory recently identified epithelial cell transforming sequence 2 (Ect2) as the key regulator of mitotic rounding. Strikingly, Ect2 is an oncogene capable of transforming NIH/3T3 fibroblasts and inducing anchorage-independent growth and invasion in NSCLC in vitro. In addition, Ect2 overexpression has been associated with a number of cancers and with a poor prognosis. In some cases Ect2 over-expression is a direct consequence of oncogenic transformation whilst, in others, Ect2 appears to drive oncogenic signalling as well as cell division. As unrestrained mitotic ability is fundamental to metastatic growth, we hypothesise that cancer cells exploit Ect2-dependent mitotic rounding to enhance their metastatic potential. We anticipate that a greater understanding of the biological mechanisms that underlie the key features of the metastatic phenotype may provide novel therapeutic targets and improve patient outcomes.
Building on preliminary data generated over the last 2 years through an ongoing collaboration between the Baum and Meyer labs, this project aims to explore the role of mitotic rounding in cancer cell metastasis. More specifically, by studying cell division in cell culture models and in patient derived tumour cells we aim to:
Determine the role of oncogenic transformation and Ect2 overexpression in facilitating mitotic rounding in models of metastatic cancer and in patient-derived tumour cells
Examine the environmental dependence of division in single cancer cells and cancer cell clusters in micro-fabricated chambers
Identify inhibitors that can be used to perturb this process to prevent cells from dividing outside of their normal mechano-chemical niche
Informal enquiries to Professor Buzz Baum firstname.lastname@example.org
1. Matthews HK et al. The metastatic cancer cell cortex: an adaptation to enhance robust cell division in novel environments? Bioessays 2012;34(12):1017-20
2. Lancaster O et al. Mitotic rounding alters cell geometry to ensure efficient bipolar spindle formation. Dev Cell 2013; 25, 270–283
3. Matthews HK et al. Changes in Ect2 Localization
Couple Actomyosin-Dependent Cell Shape Changes to Mitotic Progression. Dev Cell 2012; 23: 371–383
Physicians who are GMC-registered, meet UCL general admissions criteria, and qualify as UK/EU fee payers. These three year PhD studentships, funded by Cancer Research UK, includes a competitive clinical training salary, consumables funding, a travel allowance, and tuition fees (home/EU rate) paid in full.
To apply please e-mail the following pieces of information to CI.Crukcentre@ucl.ac.uk and provide the project number(s)* in the subject line.
1. A CV highlighting your academic achievement, clinical training, and research interest/experience, as well as stating your nationality and usual country of residence
2. A short summary (<500 words) detailing how your research interests and academic background matches the project
3. Contact details for two referees
*One application per candidate please. Although you may list more than one project per application, your short summary will need to specify how your background/interests fit each project.
Application Deadline: Applications accepted until 5.00pm 12th February 2015
Initial receipt of your application will be acknowledged. Short-listing and interviews to be done in February/March 2016. Queries about the application procedure or recruitment process should be directed to: CI.Crukcentre@ucl.ac.uk
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