2. Academic Validation
  3. Co-targeting BMI1 and MYC to eliminate cancer stem cells in squamous cell carcinoma

Co-targeting BMI1 and MYC to eliminate cancer stem cells in squamous cell carcinoma

  • Cell Rep Med. 2025 May 20;6(5):102077. doi: 10.1016/j.xcrm.2025.102077.
Zhen Qin 1,  Shuo Liu 1,  Yunfei Zheng 2,  Yujia Wang 1,  Yiwen Chen 1,  Xin Peng 3,  Lingfei Jia 4
Affiliations

Affiliations

  • 1 Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, P.R. China.
  • 2 Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing 100081, P.R. China.
  • 3 Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, P.R. China. Electronic address: pxpengxin@263.net.
  • 4 Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, P.R. China; National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, P.R. China; Beijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Institute of Advanced Clinical Medicine, Peking University, Beijing 100091, P.R. China. Electronic address: jialingfei1984@sina.com.
PMID: 40239645 DOI: 10.1016/j.xcrm.2025.102077
Abstract

BMI1+ tumor cells act as Cancer Stem Cells (CSCs) driving relapse and therapy resistance in head and neck squamous cell carcinoma (HNSCC). Although BMI1 inhibitors reduce CSCs, combined cisplatin treatment targeting non-stem tumor cells is more effective in eliminating CSCs. Non-stem tumor cells may revert to CSCs post-treatment. However, in vivo evidence and underlying mechanisms remain unclear. Here, we demonstrate that BMI1 inhibitors induce temporary tumor regression followed by relapse. Lineage tracing reveals that keratin 16-marked non-stem tumor cells revert to BMI1+ CSCs, which drive compensatory tumor growth after BMI1 targeting therapy. Mechanistically, BMI1 inhibitors activate DNA damage/nuclear factor κB (NF-κB) signaling and inflammatory cytokine secretion, subsequently stimulating myelocytomatosis viral oncogene homolog (MYC) expression in non-stem tumor cells to promote the reversion process. Genetic and pharmacological inhibition of MYC synergizes with BMI1 targeting, achieving sustained CSC eradication and relapse prevention. These findings provide insights into CSCs' plasticity and suggest dual BMI1/MYC blockade as an effective HNSCC treatment strategy.

Keywords

BMI1; IL-6; MYC; NF-κB; cancer stem cells; head and neck squamous cell carcinoma; keratin 16.

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