The role of calcium signalling in regulating of tumour cell behaviour at University of Nottingham on FindAPhD.com

Dr M Georgiou, Dr Isabella Maiellaro Applications accepted all year round Self-Funded PhD Students Only

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Nottingham United Kingdom Biochemistry Genetics Molecular Biology Molecular Genetics

School of Life Sciences, University of Nottingham

About the Project

Metastasis is the major cause of mortality in human cancers, yet we know relatively little of the fundamental biology that underlies the important transition to invasive malignancy. This project offers a PhD student the exciting opportunity to use the fruit fly (Drosophila melanogaster) to integrate sophisticated genetic, optogenetic, and imaging techniques to further our understanding of tumourigenesis, tumour progression and invasion. Significantly, this is one of the few model systems in which it is possible to characterise the precise molecular and cellular biological events that lead to the development of a malignant tumour.

Nearly 75% of human disease-causing genes have a functional homologue in the fly and many fundamental cell biological and physiological processes are highly conserved. This has led to the fly being increasingly used as a model to study human cancer. In particular, the Drosophila system we have developed will allow us to investigate the fundamental mechanisms that underly specific tumour behaviours (e.g., multilayering, invasion, survival) and identify novel genes that are relevant to human disease, which will act as potential targets for therapeutic intervention.

Calcium is a universal second messenger implicated in multiple cell functions across all kingdoms of life. In particular calcium signalling is a crucial regulator of processes associated with tumour progression. Despite its importance, our understanding of calcium spatiotemporal dynamics, which determine its functions and switch from physiology and pathology, is limited.

We have the ability to generate and visualise tumours with specific behaviours, in the living fly, through the introduction of distinct genetic lesions. We are additionally able to visualise with spatial and temporal accuracy calcium signalling within these tumourigenic cells. In this project the student will use this system to improve our understanding of the highly conserved molecular machinery underlying changes to tumour behaviour that lead toward malignancy.

This project offers the student a fantastic opportunity to learn state-of-the-art techniques, including:

· Sophisticated fly genetics

· Live high-resolution imaging using confocal and light-sheet microscopy

· Fly pupal mounting and dissections

· Immunohistochemistry

· Advanced optogenetic techniques

· Use of specialised imaging software

· A wide variety of molecular biology techniques

· Data analysis

· Statistical analysis and numeracy skills

References

• BRENDA CANALES COUTIÑO, EMMA SZAMEK, ZSUZSA MARKUS and MARIOS GEORGIOU, 2021. Generation and live imaging of tumors with specific genotypes in the living fly pupa STAR Protocols. 2(3), 100672
• RUSU, ALEXANDRA D, CORNHILL, ZOE E, COUTINO, BRENDA CANALES, URIBE, MARCOS CASTELLANOS, LOURDUSAMY, ANBARASU, MARKUS, ZSUZSA, MAY, SEAN T, RAHMAN, RUMAN and GEORGIOU, MARIOS, 2021. CG7379 and ING1 suppress cancer cell invasion by maintaining cell-cell junction integrity. Open biology. 11(9), 210077
• RUSU, ALEXANDRA D. and GEORGIOU, MARIOS, 2020. The multifarious regulation of the apical junctional complex OPEN BIOLOGY. 10(2),
• COUTINO, BRENDA CANALES, CORNHILL, ZOE E., COUTO, AFRICA, MACK, NATALIE A., RUSU, ALEXANDRA D., NAGARAJAN, USHA, FAN, YUEN NGAN, HADJICHARALAMBOUS, MARINA R., URIBE, MARCOS CASTELLANOS, BURROWS, AMY, LOURDUSAMY, ANBARASU, RAHMAN, RUMAN, MAY, SEAN T. and GEORGIOU, MARIOS, 2020. A Genetic Analysis of Tumor Progression in Drosophila Identifies the Cohesin Complex as a Suppressor of Individual and Collective Cell Invasion ISCIENCE. 23(6),
• COUTO A, MACK NA, FAVIA L and GEORGIOU M, 2017. An apicobasal gradient of Rac activity determines protrusion form and position. Nature communications. 8, 15385
• PAKKIRISWAMI, SHANMUGASUNDARAM, COUTO, AFRICA, NAGARAJAN, USHA and GEORGIOU, MARIOS, 2016. Glycosylated Notch and Cancer Frontiers in Oncology. 6,
• MACK NA and GEORGIOU M, 2014. The interdependence of the Rho GTPases and apicobasal cell polarity. Small GTPases. 5(2), 10
• BAUM, B. and GEORGIOU, M., 2011. Dynamics of adherens junctions in epithelial establishment, maintenance, and remodeling Journal of Cell Biology. 192(6), 907-917
• COHEN, M., GEORGIOU, M., STEVENSON, N.L., MIODOWNIK, M. and BAUM, B., 2010. Dynamic filopodia transmit intermittent Delta-Notch signaling to drive pattern refinement during lateral inhibition Developmental Cell. 19(1), 78-89
• GEORGIOU, M. and BAUM, B., 2010. Polarity proteins and Rho GTPases cooperate to spatially organise epithelial actin-based protrusions Journal of Cell Science. 123(7), 1089-1098
• GEORGIOU, M., MARINARI, E., BURDEN, J. and BAUM, B., 2008. Cdc42, Par6, and aPKC regulate Arp2/3-mediated endocytosis to control local adherens junction stability Current Biology. 18(21), 1631-1638
• Anton SE, Kayser C, Maiellaro I$, Nemec K, Möller J, Koschinski A, Zaccolo M, Annibale P, Falcke M, Lohse MJ, Bock A (2022) “Receptor-associated independent cAMP nanodomains mediate spatiotemporal specificity of GPCR signaling” Cell Mar 31;185(7):1130-1142.e11.
• Maiellaro I* ( 2021) “In Vivo cAMP Dynamics in Drosophila Larval Neurons.” Methods Mol Biol. 2022;2483:181-194.
• Bock A, Annibale P, Konrad C, Hannawacker A, Anton SE, Maiellaro I, Zabel U, Sivaramakrishnan S, Falcke M, Lohse MJ ( 2021) “Optical Mapping of cAMP Signaling at the Nanometer Scale.” Cell. 13;184(10):2793.
• Scholz N, Guan C, Nieberler M, Grotemeyer A, Maiellaro I, Gao S, Beck S, Pawlak M, Sauer M, Asan E, Rothemund S, Winkler J, Prömel S, Nagel G, Langenhan T, Kittel RJ (2017) “Mechano-dependent signaling by Latrophilin/CIRL quenches cAMP in proprioceptive neurons” Elife. 8;6:e28360.