Double-sided niche regulation in skin stem cell and cancer: mechanisms and clinical applications

Abstract

The niche microenvironment plays a crucial role in regulating the fate of normal skin stem cells (SSCs) and cancer stem cells (CSCs). Therapeutically targeting the CSC niche holds promise as an effective strategy; however, the dual effects of shared SSC niche signaling in CSCs have contributed to the aggressive characteristics of tumors and poor survival rates in skin cancer patients. The lack of a clear underlying mechanism has significantly hindered drug development for effective treatment. This article explores recent advances in understanding how niche factors regulate cell fate determination between skin stem cells and skin CSCs, along with their clinical implications. The dual roles of key components of the adhesive niche, including the dermo-epidermal junction and adherens junction, various cell types—especially immune cells and fibroblasts—as well as major signaling pathways such as Sonic hedgehog (Shh), Wingless-related integration site (Wnt)/β-catenin, YAP (Yes-associated protein)/TAZ (transcriptional coactivator with PDZ-binding motif), and Notch, are highlighted. Additionally, recent advances in clinical trials and drug development targeting these pathways are discussed. Overall, this review provides valuable insights into the complex interactions between skin cancer stem cells and their microenvironment, laying the groundwork for future research and clinical strategies.