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  Molecular mechanism of vimentin induced epithelial mesenchymal transition (EMT) and stemness in cancer cells


   Institute of Dentistry

  , ,  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Background: Most cancers are epithelial in origin and arise from a single progenitor cell, similar to an embryo, to become a clone of cells. When cancer cells start to invade (or undergo metastasis) the surrounding and distant tissues, they undergo a type of epithelial mesenchymal transition (EMT) classified as type 3 EMT, whereby epithelial characteristics such as apicobasal polarity, expression of keratins, E-cadherins are suppressed and mesenchymal features such as expression of vimentin, N-cadherin, b-catenin are induced along with a number of transcription factors such as Snail, Slug, Twist, enabling these cells to migrate and invade (Kalluri and Weinberg, 2009).

Recently we proposed a hypothesis that vimentin is the driving force for changes seen during EMT in metastatic cancers (Usman et al 2021). We showed that wildtype vimentin was able to increase migration and suppress keratin expression when expressed in vimentin deficient cancer cells, thus mimicking some aspects of EMT (Paccione et al 2008; Usman et al 2022). Recently a mutant vimentin in cancer cells increased proliferation by 90-fold, reduced cell adhesion, increased cell migration, invasion and suppressed keratin expression. Interestingly, the mutant vimentin also increased expression of transcription factors Twist, Slug, the long non-coding RNA XIST and became tumorigenic in nude mice. These experiments led us to suggests that the mutant vimentin was not only oncogenic but also increased stemness of cancer stem cells.

The purpose of this research proposal is to define the molecular mechanism that allows mutant vimentin to induce EMT and stemness in cancer stem cells.

Research Aims: Specific aims of the proposal are as follows:

1. To determine whether the mutant vimentin has made cancer cells resistant to apoptosis in response to exposure of genotoxic substances such as cisplatin, doxorubicin and tamoxifen.

2. To determine whether the mutant vimentin has made cancer cells angiogenic in tube forming assays for angiogenesis.

3. To determine whether the mutant vimentin has suppressed the epithelial characteristics by dysregulating AP-1 transcription factor.

4. To determine whether the mutant vimentin has dysregulated p53 pathways to increase cell proliferation.

5. To determine whether the mutant vimentin has increased cancer cell stemness by comparing spheroid formation and expression of stem cell markers.

Expected outcome: If mutant vimentin can induce EMT and increase stemness then these cells can replace animals for cancer drug screening. It would also make vimentin a therapeutic target in studies going forward.

Techniques to be employed: The project will utilise molecular cloning, site-directed mutagenesis, 2-D and 3-D cultures, cell migration, invasion and cell proliferation assays, flow cytometry, immunocytochemistry, fluorescence imaging including confocal microscopy, live cell imaging, western blotting, retroviral packaging, retroviral transduction, qRT-PCR, single cell and bulk transcriptome analyses, cytokine profiling, microRNA profiling, angiogenesis assays and animal experiments.

Admissions Requirements

A graduate with at least an upper second-class honours degree or a distinction in an experimental MSc degree is required for this PhD project. The candidate should have strong interest and preferably some experience in cell and molecular biology, pharmacology, pharmacy, biochemistry, biotechnology or biomedical sciences.

If English is not your first language, the standard requirement for English is an IELTS score of 6.5 overall for non-clinical projects and 7 overall for clinical projects (or equivalent). More details about language requirements can be found here.

 For more information on the project, please contact Prof Ahmed Waseem ()

 For information on the application process, please contact


Biological Sciences (4) Medicine (26)

Funding Notes

We will consider applications from prospective students with a source of funding to cover tuition fees and bench fees for three years full-time or 6 years part-time. Both self-funded and sponsored students will be considered.
UK nationals, Irish citizens and those with settled status under the EU Settlement Scheme or indefinite leave to remain in the UK might be eligible for a doctoral loan for both the cost of tuition fees and a yearly stipend over the course of the PhD programme from Student Finance England: View Website

References

Kalluri R and Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119: 1420–1428.
Usman, S.; Waseem, N.H.; Nguyen, T.K.N.; Mohsin, S.; Jamal, A.; Teh, M.-T.; Waseem, A (2021) Vimentin Is at the Heart of Epithelial Mesenchymal Transition (EMT) Mediated Metastasis. Cancers 13, 4985.
Paccione RJ, Miyazaki H, Patel V, Waseem A, Gutkind JS, Zehner ZE, Yeudall WA (2008). Keratin down-regulation in vimentin-positive cancer cells is reversible by vimentin RNA interference, which inhibits growth and motility. Mol Cancer Ther 7:2894-903.
Usman, S.; Jamal, A.; Bushaala, A.; Waseem, N.H.; Al-Dehlawi, H.; Yeudall, W.A.; Teh, M.-T.; Tummala, H.; Waseem, A. (2022) Transcriptome Analysis Reveals Vimentin-Induced Disruption of Cell–Cell Associations Augments Breast Cancer Cell Migration. Cells 11, 4035.

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