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Understanding the glycobiology of metastatic breast cancer by chemical biology

  • Full or part time
    Dr I Malanchi
    Dr B Schumann
  • Application Deadline
    Tuesday, November 12, 2019
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

A joint Crick-Imperial College London funded PhD position for the 2020 programme between the labs of Ilaria Malanchi and Ben Schumann.

Glycosylation is the most complex posttranslational protein modification. As the outermost component of the cell surface, glycans partake in essential cell-cell and cell-matrix interactions. These interactions are of particular relevance in the metastatic process, where cancer cells adapt to a sequence of fundamentally different cellular environments. Glycoproteins such as mucins are essential to the metastatic programme [1], hosting glycans that are structurally altered with respect to normal tissue [2]. However, the molecular details of glycoproteome alterations in cancer metastasis are still elusive. Notably, as glycoproteins are exposed on the cell membrane, the underlining mechanisms of their impact on cancer growth and progression can be both intrinsic (by changing intracellular pathways) or extrinsic (by changes in the interaction with surrounding tissue). Both aspects will be investigated.

Due to their nature as secondary gene products, the biosynthesis of glycans is encoded by the combinatorial activity of >200 glycosyltransferases (GTs) in the secretory pathway. The complex interplay of GTs renders classical methods of molecular cell biology of limited use to understand the alterations in glycan biosynthesis during cancer metastasis.

Here, a chemical biology method is used to unravel the role of glycosylation during the metastatic process. In a GT engineering approach pioneered by Ben Schumann [3, 4] and available in the Chemical Glycobiology Laboratory, cells are adorned with the capacity to tag substrates of individual GTs with chemical, bioorthogonal functionalities. Thereby, glycosyltransferases are engineered to accommodate chemically modified substrates that are delivered to the living cell using synthetic precursors. Combined with modern methods of proteomics and genome engineering, the strategy will be used to reveal the implications of glycoproteins during metastasis formation. Ilaria Malanchi is spearheading research into the molecular mechanisms of metastatic breast cancer [5] in the Tumour-Host Interaction Laboratory. Suitable glycoprotein hits will be evaluated using a range of in vitro and in vivo methods.

This project is suitable for outstanding candidates with a strong interest in understanding mechanisms sustaining cancer stemness and cancer–tissue cell interactions.

The project will suit candidates with a strong background in Biochemistry, Chemical Biology or Cell Biology and a keen interest in multidisciplinary research. The student should be proficient in methods of molecular and cell biology, as well as protein biochemistry Experience in CRISPR-based genome engineering is an additional advantage.

Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2020 and will register for their PhD at Imperial College London.

In addition to meeting the standard Crick academic eligibility criteria applicants to this position will be expected to hold either a 4-year MSci degree (at 2.1 level or higher), or a 3-year undergraduate degree plus a Masters degree. Non-EU applicants are not eligible for the funding for this project.

APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘APPLY NOW’ LINK ABOVE) BY 12:00 (NOON) 13 NOVEMBER 2019. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.

Funding Notes

In addition to meeting the standard Crick academic eligibility criteria applicants to this position will be expected to hold either a 4-year MSci degree (at 2.1 level or higher), or a 3-year undergraduate degree plus a Masters degree. Non-EU applicants are not eligible for the funding for this project.

Successful applicants will be awarded a non-taxable annual stipend of £22,000 plus payment of university tuition fees. Students of all nationalities are eligible to apply.

References

1.       Woods, E. C., Kai, F., Barnes, J. M., Pedram, K., Pickup, M. W., Hollander, M. J., . . . Bertozzi, C. R. (2017)

          A bulky glycocalyx fosters metastasis formation by promoting G1 cell cycle progression.

          eLife 6: e25752. PubMed abstract

2.       Burchell, J. M., Beatson, R., Graham, R., Taylor-Papadimitriou, J. and Tajadura-Ortega, V. (2018)

          O-linked mucin-type glycosylation in breast cancer.

          Biochemical Society Transactions 46: 779-788. PubMed abstract

3.       Choi, J., Wagner, L. J. S., Timmermans, S. B. P. E., Malaker, S. A., Schumann, B., Gray, M. A., . . . Bertozzi, C. R. (2019)

          Engineering orthogonal polypeptide GalNAc-transferase and UDP-sugar pairs.

          Journal of the American Chemical Society 141: 13442-13453. PubMed abstract

4.       Schumann, B., Malaker, S. A., Wisnovsky, S. P., Debets, M. F., Agbay, A. J., Fernandez, D., . . . Bertozzi, C. R. (2019)

          Preprint: Chemical precision glyco-mutagenesis by glycosyltransferase engineering in living cells.

          Available at: BioRxiv. https://www.biorxiv.org/content/biorxiv/early/2019/06/13/669861.full.pdf

5.       del Pozo Martin, Y., Park, D., Ramachandran, A., Ombrato, L., Calvo, F., Chakravarty, P., . . . Malanchi, I. (2015)

          Mesenchymal cancer cell-stroma crosstalk promotes niche activation, epithelial reversion, and metastatic colonization.

          Cell Reports 13: 2456-2469. PubMed abstract

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