Cancer stem cells (CSCs) are pervasively present in human cancers and have a fundamental role in treatment failure and disease recurrence. Identifying critical elements that sustain the CSC phenotype may lead to novel strategies for cancer treatment. Here, we provide evidence of an essential link between the σ1 receptor (σ1R), a ligand-regulated chaperone protein residing preferentially at the endoplasmic reticulum-mitochondria contact sites, and CSCs in castration-resistant prostate cancers (CRPCs). Integrating functional assays in multiple preclinical models with transcriptomic and proteomic data, we found that σ1R controls CSC self-renewal capacity and tumorigenic proficiency by coordinating mitochondrial dynamics and mitochondrial-nuclear signaling. Inhibiting σ1R with synthetic antagonists and RNA interference led to the progressive exhaustion and loss of tumorigenicity of the CSC progeny. Mechanistically, interfering with σ1R function disrupted mitochondria homeostasis and triggered β-catenin degradation. Examining clinical CRPC samples, we found a tight correlation between σ1R and mitochondrial gene expression. Furthermore, σ1R and β-catenin protein levels were highly correlated in prostate tumors with significant upregulation in metastatic CRPCs, sustaining a role of the σ1R-mitochondria-β-catenin axis in disease progression. This σ1R-centered axis is essential for preserving the self-renewal and tumorigenic capability of CSCs and represents a critical vulnerability exploitable for discovering novel CSC-directed therapies.
