Enhanced basal autophagy supports ameloblastoma-derived cell survival and reactivation

Rachel C Sharp; Olajumoke A Effiom; Anuradha Dhingra; Onatolu Odukoya; Adetokunbo Olawuyi; Godwin T Arotiba; Kathleen Boesze-Battaglia; Sunday O Akintoye

doi:10.1016/j.archoralbio.2018.11.013

Enhanced basal autophagy supports ameloblastoma-derived cell survival and reactivation

Arch Oral Biol. 2019 Feb:98:61-67. doi: 10.1016/j.archoralbio.2018.11.013. Epub 2018 Nov 14.

Authors

Rachel C Sharp¹, Olajumoke A Effiom², Anuradha Dhingra¹, Onatolu Odukoya², Adetokunbo Olawuyi², Godwin T Arotiba³, Kathleen Boesze-Battaglia¹, Sunday O Akintoye⁴

Affiliations

¹ Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia PA USA.
² Department of Oral and Maxillofacial Pathology/Biology, Faculty of Dental Sciences, University of Lagos, Lagos Nigeria.
³ Department of Oral and Maxillofacial Surgery, Faculty of Dental Sciences, University of Lagos, Lagos Nigeria.
⁴ Department of Oral Medicine, School of Dental Medicine, University of Pennsylvania, Philadelphia PA USA. Electronic address: [email protected].

Abstract

Objectives: Ameloblastoma is an aggressive odontogenic jaw neoplasm. Its unlimited growth confers high potential for malignant transformation and recurrence. It is unclear why ameloblastoma is highly recurrent despite surgical resection with a wide margin of normal tissue. While canonical autophagy can be used to degrade and eliminate damaged cellular components, it is also a protective mechanism that provides energy and vital metabolites for cell survival. We used ameloblastoma-derived cells to test the hypothesis that autophagic processes play a role in survival and reactivation of ameloblastoma.

Methods: Primary epithelial (EP-AMCs) and mesenchymal (MS-AMCs) ameloblastoma-derived cells were established from tissue samples of solid multicystic ameloblastoma. Clonogenic capacity and basal autophagic capacity were assessed in ameloblastoma-derived cells relative to human odontoma-derived cells (HODCs) and maxilla-mesenchymal stem cells (MX-MSCs). Ability of ameloblastoma-derived cells to survive and form new ameloblastoma was assessed in mouse tumor xenografts.

Results: EP-AMCs were highly clonogenic (p < 0.0001) and demonstrated enhanced basal levels of autophagic proteins microtubule-associated protein 1-light chain 3 (LC3) (p < 0.01), p62 (Sequestosome 1, SQSTM1) (p < 0.01), and the LC3-adapter, melanoregulin (MREG) (p < 0.05) relative to controls. EP-AMCs xenografts regenerated solid ameloblastoma-like tumor with histological features of columnar ameloblast-like cells, loose stellate reticulum-like cells and regions of cystic degeneration characteristic of follicular variant of solid multicystic ameloblastoma. The xenografts also displayed stromal epithelial invaginations strongly reactive to LC3 and p62 suggestive of epithelial-mesenchymal transition and neoplastic odontogenic epithelium.

Conclusions: EP-AMCs exhibit altered autophagic processes that can support survival and recurrence of post-surgical ameloblastoma cells.

Keywords: Ameloblastoma; Autophagy; Recurrence; Survival.

MeSH terms

Adaptor Proteins, Vesicular Transport
Ameloblastoma* / pathology
Ameloblasts / metabolism
Ameloblasts / pathology
Animals
Autophagy / physiology*
Carrier Proteins / metabolism
Cell Survival*
Disease Models, Animal
Epithelial-Mesenchymal Transition
Epithelium / metabolism
Female
Heterografts
Humans
Intracellular Signaling Peptides and Proteins
Mesenchymal Stem Cells
Mice
Microtubule-Associated Proteins / metabolism
Neoplasm Recurrence, Local
Odontogenic Tumors*
Sequestosome-1 Protein / metabolism
Xenograft Model Antitumor Assays

Substances

Adaptor Proteins, Vesicular Transport
Carrier Proteins
Intracellular Signaling Peptides and Proteins
Map1lc3b protein, mouse
Microtubule-Associated Proteins
Sequestosome-1 Protein
Sqstm1 protein, mouse
melanoregulin protein, mouse

Grants and funding

R01 DE022465/DE/NIDCR NIH HHS/United States