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A ‘Metastasis-On-A-Chip’ Microphysiological Model of Cancer Metastasis to Bone


Faculty of Biological Sciences

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Dr Mahetab Amer , Dr V Pensabene , Prof F Meldrum No more applications being accepted Funded PhD Project (European/UK Students Only)

About the Project

Bone is a frequent site of cancer metastases and usually indicates poor clinical prognosis. Metastasis of tumour cells in the bone marrow is a dynamic process, and cell behaviour is regulated by three-dimensional (3D) cell-cell and cell-matrix interactions with its microenvironment. Disseminated tumour cells can enter a period of dormancy before subsequent re-activation. Our understanding of how certain aspects of the bone microenvironment promote migration, survival and proliferation of cancer cells in bone remains poor, and there are currently no effective treatments targeting dormancy.

Recent studies have shown that breast and prostate cancer cells preferentially localize to regions of active bone formation. However, our current understanding of the interactions between specific components of the bone/bone marrow microenvironment and metastasis is limited, partly due to a lack of clinically relevant model systems which recapitulate human spatial and temporal signals within metastatic niche establishment in bone. Moreover, the underlying roles of hydroxyapatite - a key component of bone mineral matrix and breast microcalcifications- remain unclear.

The main aim of this multidisciplinary 3.5-year PhD project is to develop customisable, mineralised organ-on-a-chip models of bone metastasis to explore the bidirectional 3D cell-cell and cell-matrix interactions within bone/bone marrow niches during cancer metastasis. These models will have precisely tuned mechanical/fluidic environments and will contain varying patterns of matrix-inspired and cellular cues. This will provide unique insight into the early stages of metastasis, and will allow the exploration of potential microenvironment-based characteristics that modulate cancer cell migration and allow dormancy and reactivation.

The successful candidate will be based at the School of Molecular and Cellular Biology (Faculty of Biological Sciences) at the University of Leeds. You will work under the supervision of Dr Mahetab Amer (https://biologicalsciences.leeds.ac.uk/biological-sciences/staff/1527/dr-mahetab-h-amer), and will work closely with Pensabene (School of Electronic and Electrical Engineering) and Meldrum (School of Chemistry) research groups. This will allow the unique opportunity of working at the interface of microdevice fabrication, tissue engineering, chemistry and cancer biology. The findings will establish improved approaches for studying the pathogenesis of cancer metastasis and for developing high-throughput models to test new therapies.

The PhD project will integrate a range of approaches including microfluidics engineering, tissue engineering and 3D cell culture techniques, materials chemistry, molecular analysis, and advanced imaging. This will be used for qualitative and quantitative evaluation of the interactions between cancer and host cells and the extracellular matrix, and how physicochemical properties of bone matrix and breast calcification may favour tumour cell seeding and impact metastatic potential at both primary and secondary (bone) sites.

Requirements: This is a PhD suitable for an individual with drive and enthusiasm for working at the interface of physical sciences and cancer biology, and is particularly suited to those with an interest in multidisciplinary, translational research. Cell culture experience would be highly advantageous. You will be able to access state-of-the-art facilities in vibrant laboratory settings. Microfluidic platforms will be developed and fabricated in the Pensabene Laboratory, and micro-scale biomineralisation techniques will be carried out in the Meldrum laboratory. Cell culture, exploration of appropriate tissue engineering and cell-material interactions-based approaches, and characterisation of cellular response will be conducted in the Amer laboratory, where the student will be trained on tissue engineering-based methodologies, such as 3D cell culture, biomaterials fabrication, characterisation of cell-material interactions and biological/physical cues that drive cell response, as well as statistical analysis.

Eligibility
You should hold a first-degree, equivalent to at least a UK upper-second class honours degree, or a MSc degree in a relevant subject. This project would suit someone with a strong background in cancer biology, tissue engineering or closely-related areas. Additional experience of conducting research in a multidisciplinary setting is highly desirable. Upon completion of the PhD, the successful candidate will be uniquely equipped for high-demand careers within academia or industry with desirable skills in bioengineering and cancer cell biology.

https://phd.leeds.ac.uk/project/786-a-metastasis-on-a-chip-microphysiological-model-of-cancer-metastasis-to-bone

Funding Notes

This is a fully funded studentship, providing UK/EU fees plus stipend for 3.5 years.

References

1. Alvarez-Paino, M., Amer, M., Nasir, A., Cuzzucoli Crucitti, V., Thorpe, J., Burroughs, L., Needham, D., Denning, C., Alexander, M., Alexander, C., and Rose, F.; Polymer Microparticles with Defined Surface Chemistry and Topography Mediate the Formation of Stem Cell Aggregates and Cardiomyocyte Function. ACS Appl. Mater. Interfaces 2019 11 (38), 34560-34574
2. Croucher, P., McDonald, M. & Martin, T.; Bone metastasis: the importance of the neighbourhood. Nat Rev Cancer 2016 16, 373–386
3. Brown J, Pensabene V, Markov D, Allwardt V, Neely M, Shi M, Britt C, Hoilett O, Yang Q, Brewer B, Samson P, McCawley L, May J, Webb D, Li D, Bowman A, Reiserer R, Wikswo J; Recreating blood-brain barrier physiology and structure on chip: A novel neurovascular microfluidic bioreactor. Biomicrofluidics 2015.
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