In the last decade, organoid technology has emerged as a powerful tool to study human diseases in 3D. In the oral mucosa, genetic changes can prompt extracellular matrix remodelling, leading to epithelial mesenchymal transition and cancer, but it’s not clear how these signals are regulated. Advances in biomaterials, especially the development of hydrogels with tuneable physiochemical properties, offer the opportunity to model the native extracellular matrix microenvironment. This project aims to use fully synthetic hydrogels incorporating a FRET-based sensor of matrix metalloproteinase (MMP) activity combined with 3D oral mucosal organoid models to quantitatively analyse how extracellular matrix remodelling is driven by specific genetic changes. Our aim is to understand how the oral mucosa regulates extracellular matrix degradation and contributes epithelial mesenchymal transition.
1 Sequeira I, Rashid M, Tomas I, Williams M, Graham T, Adams D, Vigilante A, Watt FM (2020). The genomic landscape and clonal selection of carcinogen-induced mouse oral squamous cell carcinoma. Nature Communications. doi:10.1038/s41467-020-19401-9
2 Hisha H, Tanaka T, Kanno S, et al (2013) Establishment of a novel lingual organoid culture system: generation of organoids having mature keratinized epithelium from adult epithelial stem cells. Sci Rep 3:3224. doi: 10.1038/srep03224
3 Driehuis E, Kolders S, Spelier S, Lohmussaar K, Willems SM, Devriese LA et al. Oral Mucosal Organoids as a Potential Platform for Personalized Cancer Therapy. Cancer Discov. 2019;9(7):852-71. doi:10.1158/2159-8290.CD-18-1522.
4 Jowett GM, Norman MDA, Yu TTL, Arévalo PR, Hoogland D, Lust S, Read E, Hamrud E, Walters NJ, Niazi U, Chung MWH, Marciano D, Omer OS, Zabinski T, Danovi D, Lord GM, Hilborn J, Evans ND, Dreiss C, Bozec L, Oommen OP, Lorenz C, Silva RMP, Neves JF*, Gentleman E*. ILC1 drives intestinal and matrix remodelling. Nature Materials. 2021 Feb;20(2):250-259 *co-senior & co-corresponding authors