ORIGINAL RESEARCH article
Front. Oral. Health
Sec. Oral Cancers
Volume 6 - 2025 | doi: 10.3389/froh.2025.1570042
This article is part of the Research TopicPathophysiology and Therapeutic Strategies for Oral and Head and Neck CancersView all 11 articles
Characterization of uniquely tumorigenic cancer stem cells in salivary gland adenoid cystic carcinoma
Provisionally accepted
Kristy A. Warner
Sosuke Sahara
Alexandra Herzog
Felipe Nor
Rogerio Castilho
Peter Polverini
Jacques E. Nor*- Dentistry, University of Michigan, Ann Arbor, Michigan, United States
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Background: Cancer stem cells (CSC) are endowed with multipotency, self-renewal and unique tumorigenic potential. They have been identified as cells with high activity of aldehyde dehydrogenase (ALDH) and high expression of CD44 in head and neck squamous cell carcinoma (HNSCC). The objective of this work is to understand whether salivary gland adenoid cystic carcinoma contain CSCs and whether they exhibit a unique tumorigenic activity in this cancer.We used flow cytometry, salisphere and western blot assays with 3 human ACC cell lines (UM-HACC-2A, UM-HACC-14, UM-HACC-6) to characterize the impact of ALDH activity and CD44 expression. In vitro results were verified in vivo by orthotopic injection of cells retrieved from a patient-derived xenograft (PDX) model of ACC (UM-PDX-HACC-14) in the submandibular gland of SCID mice. Primary tumor and metastatic spread were evaluated by 2 pathologists blinded for experimental conditions.The fraction of ALDH high CD44 high cells in UM-HACC-2A, UM-HACC-14 and UM-HACC-6 ranged from 3-8%. ALDH high CD44 high cells formed more salispheres and expressed higher levels of stem cell markers (e.g. Notch2, Bmi-1) compared to control ALDH low CD44 low cells.ALDH high CD44 high cells sorted from the ACC PDX tumors were more tumorigenic upon orthotopic transplantation into submandibular salivary glands and generated more lung metastases than control ACC cells. Strong ALDH1A1 staining was observed in the majority of salivary gland tumors and lung metastases generated by transplantation of ALDH high CD44 high cells.We conclude that salivary gland adenoid cystic carcinoma contain a small population of uniquely tumorigenic cells characterized by high ALDH activity and expression.
Keywords: Salivary gland cancer, Cancer stemness, Tumor-initiating cells, Aldehyde Dehydrogenase, tumor cell heterogeneity
Received: 02 Feb 2025; Accepted: 15 Apr 2025.
Copyright: © 2025 Warner, Sahara, Herzog, Nor, Castilho, Polverini and Nor. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jacques E. Nor, Dentistry, University of Michigan, Ann Arbor, 48109, Michigan, United States
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