Advanced 3D models for Cancer Research

Radiotherapy and many chemotherapies kill cells by damaging DNA. The efficiency of these DNA damaging agents differs between tumour types and individual patients. However, it is highly influenced by the tumour microenvironment (TME). The TME is the biological, biophysical, biomechanical and biochemical environment in which the tumour exists. When studying radiotherapy or chemotherapy response it is a challenge to recreate the in vivo milieus preclinically. Traditional 2D cell culture is a simplistic and cost-effective approach to culture cells in vitro, however, it fails to recapitulate important features of the TME such as structure, hypoxia, cell-cell and cell-matrix interactions. On the other hand the use of animals in cancer therapy research creates a realistic in vivo TME but is time consuming and costly. The creation of complex 3D models using tissue engineering can capture tumour morphology, cell–cell/cell–ECM interactions, tissue stiffness, and specific chemical gradients (for example hypoxia), thus facilitating more realistic treatment response without the cost and ethical concerns of animal studies. However, currently, the application of 3D models for DNA damage response studies is limited.

We have recently shown that tissue stiffness alters the DNA damage response and response to chemotherapy in breast cancer (1). In addition we have developed novel tuneable, easy-to-manufacture polymer based materials that can be sculpted to created tumour like structures into which single and multiple cell types can be grown (2,3). These can be 3D printed into different shapes and with different sizes and stiffnesses. They can therefore be used to recreate morphologies, cell–cell/cell–ECM interactions, tissue stiffness, and hypoxic gradients known to be important for therapy response.

Here we will utilise these materials to create 3D models of 3 different tumour types, namely triple negative breast cancer (TNBC), head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC). We will then expose these to DNA damaging chemotherapeutics and radiotherapy and examine cell survival and the DNA damage response, comparing them to those seen in 2D. Once established the models will be utilized to test novel therapies, with a focus on DNA repair inhibitors (e.g. 4,5).

You will work in the labs of Dr Helen Bryant (DNA repair and Replication Lab, Department of Oncology and Metabolism) and Prof. Fred Claeyssens (Biomaterials Lab, Department of Materials Science and Engineering).

References

(1)  Grant E, Bucklain FA, Ginn L, Laity P, Ciani B, Bryant HE (2022) Progesterone receptor expression contributes to gemcitabine resistance at higher ECM stiffness in breast cancer cell lines. PLoS ONE 17(5): e0268300. https://doi.org/10.1371/journal.pone.0268300

(2) Aldemir Dikici B, Malayeri A, Sherborne C, Dikici S, Paterson T, Dew L, Hatton P, Ortega Asencio I, MacNeil S, Langford C, Cameron NR, Claeyssens F. Thiolene- and Polycaprolactone Methacrylate-Based Polymerized High Internal Phase Emulsion (PolyHIPE) Scaffolds for Tissue Engineering. Biomacromolecules. 2022 Mar 14;23(3):720-730. https://pubs.acs.org/doi/10.1021/acs.biomac.1c01129

(3) Field, J.; Haycock, J.W.; Boissonade, F.M.; Claeyssens, F. A Tuneable, Photocurable, Poly(Caprolactone)-Based Resin for Tissue Engineering—Synthesis, Characterisation and Use in Stereolithography. Molecules 2021, 26, 1199. https://doi.org/10.3390/molecules26051199

Entry Requirements:

Candidates must have a first or upper second class honors degree or significant research experience and have an interest in interdisciplinary research.

How to apply:

Please complete a University Postgraduate Research Application form available here: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying

Please clearly state the prospective main supervisor (Dr Bryant) in the respective box and select (Department of Oncology and Metabolism) as the department.

Enquiries:

Interested candidates should in the first instance contact Dr H Bryant: h.bryant@sheffield.ac.uk 

Funding:

Self funded