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Role of primary cilia in lung carcinogenesis (partially funded MPhil)

This is an MPhil Project only. Bench Fees will be covered.

Cilia are antennae-like sensory organelles that detect mechanical and chemical stimuli. The physiological importance of cilia is highlighted by the existence of a number of developmental disorders caused by ciliary defects. These disorders are known as ciliopathies and can result in cognitive impairment, hearing loss, heart and lung defects, sterility, obesity, diabetes and cancer. In 2018, my laboratory showed for the first time that primary cilia mediate a number of drug resistance mechanisms in pre-clinical lung cancer models (Jenks et al, 2018). Notably, inhibiting cilia function sensitizes lung cancer cells to clinical kinase inhibitors, providing a rationale for targeting cilia as a therapeutic strategy.

This project aims to further dissect mechanistically the role of cilia in drug resistance in lung cancer models. Furthermore, given that drug resistance mechanisms such as the activation of epithelial-to-mesenchymal-transition programmes promote metastasis, we will also explore the role of cilia in promoting cell invasion.

This project will explore the hypothesis that cilia can drive the activation of specific oncogenic signalling pathways that promote drug resistance and cell invasion in lung cancer. Expected outcomes We will characterise the role of primary cilia on modulating oncogenic signalling pathways in drug-resistant lung-cancer cells. Additionally, we will examine the role of cilia in invasion in lung cancer models, including lung cancer on chip invasion models.

Further reading

Primary cilia mediate diverse kinase inhibitor resistance mechanisms in cancer. 2018. Andrew D. Jenks, Simon Vyse, Jocelyn P. Wong, Deborah Keller, Tom Burgoyne, Amelia Shoemark, Maike de la Roche, Martin Michaelis, Jindrich Cinatl, Paul H. Huang and Barbara E. Tanos. 2018. Cell Reports. 2018 Jun 5;23(10):3042-3055. doi: 10.1016/j.celrep.2018.05.016.

How to apply

If you are interested in applying for the above PhD topic please follow the steps below:

  1. Contact the supervisor by email or phone to discuss your interest and find out if you woold be suitable. Supervisor details can be found on this topic page. The supervisor will guide you in developing the topic-specific research proposal, which will form part of your application.
  2. Click on the 'Apply here' button on this page and you will be taken to the relevant PhD course page, where you can apply using an online application.
  3. Complete the online application indicating your selected supervisor and include the research proposal for the topic you have selected.

Good luck!

This is a partially funded topic

This is an MPhil Project only. Bench Fees will be covered.

Dr Barbara Tanos - A global nomad, Dr Barbara Tanos received her undergraduate degree from the University Buenos Aires, Argentina, and her PhD in Molecular Cancer Biology from Duke University in North Carolina (USA). As a graduate student in the laboratory of Dr Ann Marie Pendergast, Dr Tanos became interested in how signal transduction pathways regulate basic biological processes such as the trafficking of growth factor receptors throughout the cell. During her graduate studies, Dr Tanos uncovered a novel role of Abl tyrosine kinases in the regulation of the epidermal growth factor receptor (EGFR) internalization through specific phosphorylation of a tyrosine residue and through the disruption of the EGFR/Cbl interaction.  During her postdoc, Dr. Tanos began conceptualizing the idea that specific signals that drive epithelial polarity can be co- opted by cancer cells to optimize the remodeling of tumor tissue architecture, she trained with world-renowned cell biologist Dr. Enrique Rodriguez-Boulan at WCMC-NY, and wrote a review entitled “The epithelial polarity program: machineries involved and their hijacking by cancer,” and also uncovered a novel role for the scaffold protein IQGAP1 in barrier function during the establishment of epithelial polarity. After this, she began to appreciate the importance of understanding signaling from centrioles and cilia, which she hypothesized, could function as signaling hubs. Since little was known about these organelles, Barbara went to the laboratory of Dr. Bryan Tsou, an expert in the field, to learn key aspects of centrosome and cilia biology. There, Barbara identified a novel group of centriolar distal appendage proteins required for cilia formation, and uncovered the mechanism and cell cycle regulation of centriole docking to the plasma membrane. This work was published in Genes and Development, has been highly cited and it is considered to be a hallmark paper in the field. The proteins she described have now been causally linked to hereditary syndromes involving cilia defects (ciliopathies). At Brunel University, Dr Tanos’s lab focuses on understanding the mechanisms of regulation of centrioles and cilia, how they function as signalling platforms, and what the consequences of their misregulation are in disease. Using a unique mix of expertise in signal transduction, biochemistry, cancer biology and cell biology she uses this information to find and exploit therapeutic opportunities both for cancer and ciliopathies. Work from the Tanos Lab,  has been recently published in Cell Reports, describing a truly novel and fascinating story on the role of primary cilia in promoting resistance to a variety of cancer drugs: https://www.cell.com/cell-reports/fulltext/S2211-1247(18)30749-6, and was featured in the MRC and other news websites: http://bpod.mrc.ac.uk/archive/2018/6/28, https://www.icr.ac.uk/news-archive/stunting-cell-antennae-could-make-cancer-drugs-work-again. and Dr. Tanos was interviewed on the radio, http://news.radiojackie.com/2018/06/the-institute-of-cancer-research-in.html External website: tanoslab.org