p53 Inhibits Bmi-1-driven Self-Renewal and Defines Salivary Gland Cancer Stemness

Purpose: Mucoepidermoid carcinoma (MEC) is a poorly under-stood salivary gland malignancy with limited therapeutic options. Cancer stem cells (CSC) are considered drivers of cancer progres-sion by mediating tumor recurrence and metastasis. We have shown that clinically relevant small molecule inhibitors of MDM2-p53 interaction activate p53 signaling and reduce the fraction of CSC in MEC. Here we examined the functional role of p53 in the plasticity and self-renewal of MEC CSC.Experimental Design: Using gene silencing and therapeutic activation of p53, we analyzed the cell-cycle profiles and apo-ptosis levels of CSCs in MEC cell lines (UM-HMC-1,-3A,-3B) via flow cytometry and looked at the effects on survival/self-renewal of the CSCs through sphere assays. We evaluated the effect of p53 on tumor development (N 1/4 51) and disease recurrence (N 1/4 17) using in vivo subcutaneous and orthotopic murine models of MEC. Recurrence was followed for 250 days after tumor resection.Results: Although p53 activation does not induce MEC CSC apoptosis, it reduces stemness properties such as self-renewal by regulating Bmi-1 expression and driving CSC towards differenti-ation. In contrast, downregulation of p53 causes expansion of the CSC population while promoting tumor growth. Remarkably, therapeutic activation of p53 prevented CSC-mediated tumor recurrence in preclinical trials.Conclusions: Collectively, these results demonstrate that p53 defines the stemness of MEC and suggest that therapeutic activation of p53 might have clinical utility in patients with salivary gland MEC.

Automated summary

This study reveals the crucial role of p53 in the self-renewal and plasticity of cancer stem cells (CSCs) in mucoepidermoid carcinoma (MEC). Therapeutic activation of p53 reduces the CSC fraction and prevents tumor recurrence, suggesting its clinical utility in treating salivary gland MEC.