Cancer stem cell self-renewal as a therapeutic target in human oral cancer

• Published in: Oncogene Vol. 38; no. 27; pp. 5440 - 5456
• Main Authors: Hu, Jinwei, Mirshahidi, Saied, Simental, Alfred, Lee, Steve C., De Andrade Filho, Pedro A., Peterson, Nathaniel R., Duerksen-Hughes, Penelope, Yuan, Xiangpeng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-07-2019; Nature Publishing Group
• Subjects: 13; 13/100; 13/106; 13/31; 13/95; 631/67/71; 631/80; 64/60; 82/80; 96/63; Aldehyde Dehydrogenase - metabolism; Apoptosis; Carcinoma, Squamous Cell - pathology; Carcinoma, Squamous Cell - therapy; Care and treatment; Cell Biology; Cell death; Cell Proliferation; Cell Self Renewal; Cisplatin; Development and progression; Diseases; Heterografts; Human Genetics; Humans; Internal Medicine; Medicine; Medicine & Public Health; Metastases; Metastasis; Mouth cancer; Mouth Neoplasms - pathology; Mouth Neoplasms - therapy; Neoplastic Stem Cells - cytology; Oncology; Oral cancer; Oral cavity; Polycomb Repressive Complex 1 - antagonists & inhibitors; Polycomb Repressive Complex 1 - metabolism; Proof of Concept Study; Relapse; Risk factors; Squamous cell carcinoma; Stem cells; Therapeutic applications; Tumors; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-019-0800-z

Tumor recurrence following treatment remains a major clinical challenge in oral cavity cancer. Cancer stem cells (CSCs) have been isolated from human oral cancers and been considered as the driving force of tumor recurrence and metastasis. However, it still remains unclear whether targeting CSCs in oral cancer is a clinically relevant strategy to combat cancer recurrence and metastasis. Here, using clinical cancer specimens and patient-derived xenografts, we show that the self-renewal regulator BMI1 is highly expressed in CSCs of oral cavity squamous cell carcinoma. Inhibition of BMI1 decreases oral CSCs’ self-renewal and tumor-initiating potential. Treatment of pre-established human oral cancer xenografts with a BMI1 inhibitor resulted in abrogation of tumor progression and reduced the frequency of CSCs in the xenografts. Remarkably, the BMI1 inhibitor has therapeutic effects in cisplatin-resistant tumors and can reduce metastases initiated by circulating CSCs. Mechanistically, BMI1-inhibition leads to oral CSC necroptotic cell death, which underlies the self-renewal impairment after inhibiting BMI1. Our data provide a pre-clinical proof-of-concept that targeting BMI1-related CSC self-renewal is a clinically relevant anti-cancer therapy in human oral cavity squamous cell carcinoma.