Bioengineering the ameloblastoma tumour to study its effect on bone nodule formation

• Published in: Scientific reports Vol. 11; no. 1; p. 24088
• Main Authors: Bakkalci, Deniz, Jay, Amrita, Rezaei, Azadeh, Howard, Christopher A., Haugen, Håvard Jostein, Pape, Judith, Kishida, Shosei, Kishida, Michiko, Jell, Gavin, Arnett, Timothy R., Fedele, Stefano, Cheema, Umber
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.12.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67/70; 692/308/1426; Ameloblastoma; Ameloblastoma - complications; Ameloblastoma - genetics; Ameloblastoma - physiopathology; Ameloblastoma - therapy; Animals; Bioengineering; Biomimetics; Bone growth; Bone mass; Bone resorption; Bone Resorption - etiology; Bone Resorption - therapy; Cbfa-1 protein; Collagen; Core Binding Factor Alpha 1 Subunit - genetics; Core Binding Factor Alpha 1 Subunit - metabolism; Gelatinase A; Gene Expression; Genes; Humanities and Social Sciences; Humans; Jaw Neoplasms - complications; Jaw Neoplasms - genetics; Jaw Neoplasms - physiopathology; Jaw Neoplasms - therapy; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Microenvironments; multidisciplinary; Neoplasm Invasiveness; Nodules; Osteoblasts; Osteoblasts - physiology; Osteogenesis; Phenotypes; Raman spectroscopy; RANK Ligand - genetics; RANK Ligand - metabolism; Rats; Science; Science (multidisciplinary); Stroma; Stromal Cells; Tissue Engineering - methods; Transmission electron microscopy; Tumor Cells, Cultured; Tumor Microenvironment; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-03484-5

Ameloblastoma is a benign, epithelial cancer of the jawbone, which causes bone resorption and disfigurement to patients affected. The interaction of ameloblastoma with its tumour stroma drives invasion and progression. We used stiff collagen matrices to engineer active bone forming stroma, to probe the interaction of ameloblastoma with its native tumour bone microenvironment. This bone-stroma was assessed by nano-CT, transmission electron microscopy (TEM), Raman spectroscopy and gene analysis. Furthermore, we investigated gene correlation between bone forming 3D bone stroma and ameloblastoma introduced 3D bone stroma. Ameloblastoma cells increased expression of MMP-2 and -9 and RANK temporally in 3D compared to 2D. Our 3D biomimetic model formed bone nodules of an average surface area of 0.1 mm 2 and average height of 92.37 ± 7.96 μm over 21 days. We demonstrate a woven bone phenotype with distinct mineral and matrix components and increased expression of bone formation genes in our engineered bone. Introducing ameloblastoma to the bone stroma, completely inhibited bone formation, in a spatially specific manner. Multivariate gene analysis showed that ameloblastoma cells downregulate bone formation genes such as RUNX2 . Through the development of a comprehensive bone stroma, we show that an ameloblastoma tumour mass prevents osteoblasts from forming new bone nodules and severely restricted the growth of existing bone nodules. We have identified potential pathways for this inhibition. More critically, we present novel findings on the interaction of stromal osteoblasts with ameloblastoma.