Bakkalci, Deniz; (2021) Development of a 3D Model of Ameloblastoma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Introduction: Ameloblastoma is a benign yet aggressive tumour of the jawbones causing bone resorption and has a high rate of recurrence after surgery. The precise molecular mechanisms driving ameloblastoma remain unclear and it is critical to study the association between ameloblastoma and its native bone microenvironment if we are to develop new therapeutic interventions. Current 3D ameloblastoma in vitro models lack an active bone component and there is no 3D bone model which canß biomimetically recapitulate active bone formation. Methods: First, an in vitro 3D ameloblastoma model was established and characterised the ameloblastoma cell lines within. Then a novel active bone-forming stroma model (3D bone stroma model) was created, and fully characterised bone nodules produced therein. The ameloblastoma tumour mass was placed on top of active 3D bone stroma compartments and conducted gene work to understand the genetic alterations in bone cells as well as ameloblastoma cells. Results: 3D tumouroid model successfully mimicked the ameloblastoma tumour microenvironment and native subtype cell morphology and caused ameloblastoma cells to produce more bone resorption proteins in earlier days. Then, a novel active bone-forming model was developed by forming bone nodules in 3D stiff matrix with high collagen density. This model allowed detection of early and late bone formation markers. The compositional and structural characterisation of the bone nodules was completed. The 3D bone stroma was used as a compartment of 3D ameloblastoma tumouroid model. This compartmentalised model showed that ameloblastoma directly inhibits bone nodule formation by targeting osteoblast differentiation genes and bone matrix development genes. Conclusion: The development of the first 3D ameloblastoma tumouroid model with of active bone stroma provided novel information about ameloblastoma microenvironment and some of the mechanisms associated with bone damage. The genes involved in ameloblastoma-induced inhibition of bone formation were identified. Further work is ongoing in order to include osteoclast-like cells in the 3D model, with a view to increase its biomimetic complexity, study the interaction between ameloblastoma cells, active bone formation cells, and osteoclasts, and explore potential drug targets.

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