Fixed-term

Details DNA damaging therapies have been successful in treating cancer patients for decades. The standard of care therapy for many cancers include small molecule inhibitors, however these therapies have widespread side-effects including; nephrotoxicity, hepatotoxicity and neurotoxicity. Greater than 25% of patients report serious side effects. There is a need to reduce toxicity in therapies. This PhD will use cell penetrating peptides, that have been shown to target cancer cells and chemically link them to small molecules that induce DNA damage. The purpose is to make novel peptide-drugs that can deliver safe therapies to patients that are highly effective. The PhD will work in both chemistry, cell biology and molecular laboratories designing and testing novel drugs. The candidate can be from either chemistry or molecular biosciences backgrounds. The PhD will use pharmacology techniques, synthesis of complex molecules, cell biology, molecular biology assays, immunological staining of cancer cells and imaging. Please apply for this project using this link: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying Funding Notes Self Funded or externally funded students only References Cirillo, S., et al., (2024) Antimicrobial peptide A9K as a gene delivery vector in cancer cells. European Journal of Pharmaceutics and Biopharmaceutics. Volume 198,114244, May, doi:10.1016/j.ejpb.2024.114244 Hadianamrei, R., et al.,. (2023) Surfactant like peptides for targeted gene delivery to cancer cells. Biochemical and Biophysical Research Communications. 652:35-45 Apr doi:10.1016/j.bbrc.2023.02.026 Cirillo, S., et al., (2021). Designed antitumor peptide for targeted siRNA delivery into cancer spheroids. ACS Applied Materials & Interfaces, 13(42), 49713-49728. doi:10.1021/acsami.1c14761 Apply Now

Details Breast and pancreatic tumours are characterised by excessive deposition of extracellular matrix (ECM) components, resulting in extensive fibrosis, which in turn promotes tumour progression and metastasis. Our lab has recently demonstrated that cancer cells, but not normal epithelial cells, are able to internalise ECM components, digest them in the lysosomes and use them as energy sources. Importantly, this process was required to promote cell growth and cell migration in both breast and pancreatic cancer cells. Therefore, identifying regulators of this process might lead to the development of novel anti-cancer therapies. Preliminary data indicate that the degradation of ECM by cathepsin proteases is required for ECM internalisation. The overall aim of this project is to elucidate the role of cathepsin in promoting cancer growth and migration, and define the molecular mechanisms behind it. In particular, this project is composed of 3 objectives: – Objective 1: we will characterise the expression of different members of the cathepsin family and elucidation of the role of specific cathepsins in controlling ECM uptake – Objective 2: as cathepsins are lysosomal protein that can be secreted, here we will define how cathepsin secretion works and whether this is stimulated during tumour progression – Objective 3: we will define the role of cathepsin in controlling cancer cell growth and invasion, using a variety of 2D and 3D cancer models. Together, this project will determine whether specific cathepsins might represent novel targets to prevent tumour growth and migration. Please apply for this project using this link: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying Funding Notes Self or externally funded students only. References Nazemi et al., PLOS Biology 2024 Martinez et al., PLOS Biology 2024 https://www.sheffield.ac.uk/biosciences/people/academic-staff/elena-rainero Apply Now

Details Mutation in the non-coding region of C9orf72 gene represents by far the most common genetic cause identified for amyotrophic lateral sclerosis (ALS), a rare, lethal, devastating but currently incurable, unstoppable and irreversible motor neuron disease. Moreover, reduced levels of C9orf72 transcript and C9orf72 (C9) expression have been associated with ALS patients, and C9orf72 is important for initiating autophagy (1), suggesting a mechanistic link between impaired autophagy and ALS pathogenesis. Intriguingly mitochondrial fission 1 protein (FIS1) is identified as a genetic interacting partner for C9 (2). FIS1 is a protein key to mitochondrial quality control and cell death induction (3, 4), and we have recently demonstrated that essential role for FIS1 for mitochondrial autophagy (mitophagy) induced by iron chelation drug deferiprone (DFP)(5, 6), which is under clinical trials (NCT02164253 and NCT03293069) for ALS treatment (7). This has led two questions: i) is C9 involved in initiating DFP-induced mitophagy? and ii) does C9 have a role in cell death mediated by FIS1? This project aims to answer the two questions. In addition to capitalising on the molecular biology, protein chemistry, imaging tools (e.g., mito-pHfluorin probe) and procedures, cell survival and death assays as well as model cell lines (WT and FIS1 knockout (KO) MEFs and WT and FIS1 KO HeLa cells) available in our lab, for manipulating cellular C9 levels, we will use validated C9 RNAi and constructs encoding C9 and C9 KO human cells as well as C9 and FIS1 binding defective mutants. With all these resources we are confident in determining the functional consequence due to the loss of C9orf72-Fis1 interaction in DFP-induced mitophagy and FIS1-induced cell death. To test the role of C9orf72 hexanucleotide in mitophagy induction by DFP and FIS1-mediated cell death, human C9 KO cells expressing C9orf72 WT and disease-causing C9orf72 mutant will be used through collaboration with Dr Hautbergue (8). Our mechanistic findings will be validated in motor-neuron-like NSC-34 cells and iPS-derived motor neurons. Outcomes from this project would reveal novel roles for C9 in mitophagy and cell death regulation and their relevance to ALS disease mechanisms. For more information about the project, or to discuss a potential application, please contact Dr Chun Guo (https://www.sheffield.ac.uk/biosciences/people/academic-staff/chun-guo; c.guo@sheffield.ac.uk) Science Graduate School As a PhD student in one of the science departments at the University of Sheffield, you’ll be part of the Science Graduate School. You’ll get access to training opportunities designed to support your career development by helping you gain professional skills that are essential in all areas of science. You’ll be able to learn how to recognise good research and research behaviour, improve your communication abilities and experience the breadth of technologies that are used in academia, industry and many related careers. Visit http://www.sheffield.ac.uk/sgs to learn more. Please apply for this project using this link: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying Funding Notes Available for self or externally funded students only. References 1. C. P. Webster et al., The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. Embo j 35, 1656-1676 (2016). DOI: 10.15252/embj.201694401 2. N. Chai et al., Genome-wide synthetic lethal CRISPR screen identifies FIS1 as a genetic interactor of ALS-linked C9ORF72. Brain research 1728, 146601 (2020). DOI: 10.1016/j.brainres.2019.146601 3. R. Iwasawa, A. L. Mahul-Mellier, C. Datler, E. Pazarentzos, S. Grimm, Fis1 and Bap31 bridge the mitochondria-ER interface to establish a platform for apoptosis induction. The EMBO journal 30, 556-568 (2011). DOI: 10.1038/emboj.2010.346 4. Q. Shen et al., Mutations in Fis1 disrupt orderly disposal of defective mitochondria. Molecular biology of the cell 25, 145-159 (2014). DOI: 10.1091/mbc.E13-09-0525 5. E. Waters et al., The SUMO protease SENP3 regulates mitochondrial autophagy mediated by Fis1. EMBO reports 23, e48754 (2022). DOI: 10.15252/embr.201948754 6. K. A. Wilkinson, C. Guo, Iron chelation promotes mitophagy through SENP3-mediated deSUMOylation of FIS1. Autophagy 18, 1743-1745 (2022). DOI: 10.1080/15548627.2022.2046898 7. C. Petillon et al., The Relevancy of Data Regarding the Metabolism of Iron to Our Understanding of Deregulated Mechanisms in ALS; Hypotheses and Pitfalls. Front Neurosci 12, 1031 (2018). DOI: 10.3389/fnins.2018.01031 8. L. M. Castelli et al., SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis. Mol Neurodegener 16, 53 (2021). DOI: 10.1186/s13024-021-00475-y Apply Now

Details Project description: Morphogenesis—the process by which tissues acquire their shape—is central to the development and function of all multicellular life. It is increasingly clear that morphogenesis is often governed by a dynamic interplay between chemical (i.e. molecular) signalling and mechanical forces. However, this integrated control, known as mechanochemical signalling, remains poorly understood in vertebrates. Skin appendages are a diverse group of micro-organs, including scales, feathers, hair and teeth, that have been widely used as model systems to investigate embryonic development. This PhD project will investigate how mechanical cues influence chemical signalling to shape the development of skin appendages in two vertebrate models: the chicken embryo, a classical system in developmental biology, and the shark embryo, an emerging model from the cartilaginous fishes. Sharks display diverse scale morphologies across their body, providing an opportunity to investigate how mechanochemical systems underpin developmental diversity. This interdisciplinary project will use 3D fluorescence microscopy, biophysical analyses, transcriptomics (RNA-sequencing), and in vivo experimentation, to investigate and compare skin appendage development between the shark and chicken. This work will advance our understanding of how mechanical and chemical signalling interact to control morphogenesis, and how mechanochemical developmental processes have evolved across distinct vertebrate lineages. Candidate requirements: We welcome applicants with a strong background in biology, biophysics, biomedical sciences, or a related field. Experience in developmental biology, microscopy, or molecular biology is desirable but not essential. Applicants should demonstrate enthusiasm for evo-devo biology and interdisciplinary research. Please apply for this project using this link: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying Funding Notes This is a self-funded project. Applicants must secure their own funding or be eligible to apply for competitive doctoral scholarships. We are happy to support strong candidates in applying for institutional, national, or international funding opportunities. References For more information or to apply, please contact Dr Rory Cooper at r.l.cooper@sheffield.ac.uk Lab website: https://rorylcooper.wordpress.com/ Institution website: https://www.sheffield.ac.uk/biosciences/people/academic-staff/rory-cooper Selected relevant publications: Santos Durán, G., Cooper, R. L., Jahanbakhsh, E., Timin, G., & Milinkovitch, M. C., Self organised Patterning of Crocodile Head Scales by Compressive Folding. Nature 2025; 637, 375-383 Cooper, R. L., & Milinkovitch M. C., In-vivo sonic hedgehog pathway antagonism temporarily results in ancestral proto-feather-like structures in the chicken. PLOS Biology 2025; 23(3): e30003061 Cooper, R. L., Thiery, A. P., Fletcher, A. G., Delbarre, D., Rasch, L. J., & Fraser, G. J., An ancient Turing-like patterning mechanism regulates skin denticle development in sharks. Science Advances 2018; 4: eaau5484 Apply Now

Details The deregulation of cell cycle progression is a common feature of cancer formation and progression. Cell/extracellular matrix (ECM) interaction is widely known to support the progression of the cells through the cell cycle. Recent data from our lab indicate that the internalisation of ECM components is promoted during the G1 phase of the cell cycle and this process is associated with an increased activation of mTOR signalling. Furthermore, we have shown that ECM uptake is, at least in part, mediated by b1 integrin, which internalisation seems to be induced when the cells are synchronised in G1 phase. These observations have been validated using the FUCCI system, a fluorescence-based reporter system which allow the visualisation of the different phases of the cell cycle without inducing any perturbation. Interestingly, cells in G1 strongly increase nucleotide synthesis, in preparation for DNA replication in S phase and our preliminary data suggest that ECM endocytosis might support nucleotide metabolism. This raises the intriguing hypothesis that ECM internalisation might support nucleotide synthesis in G1. In order to investigate this, this project will characterise: 1. The expression of known regulators of ECM internalisation and ECM receptors in the different phases of the cell cycle, to define the molecular mechanisms promoting ECM uptake in G1 2. The metabolic changes occurring in the different phases of the cell cycle, using a metabolomics approach, with a focus on nucleotide metabolism 3. The impact of ECM internalisation in controlling nucleotide synthesis Overall, this project will shed new light on how cell cycle progression is regulated, potentially identify novel therapeutic targets for the development of anti-cancer therapies. Please apply for this project using this link: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying Funding Notes Self or externally funded students only. References Nazemi et al., PLOS Biology 2024 Martinez et al., PLOS Biology 2024 https://www.sheffield.ac.uk/biosciences/people/academic-staff/elena-rainero Apply Now