Integrated control of mitochondrial dynamics and cancer cell stemness by σ1 receptor

Tumor cells endowed with cardinal stem cell properties are pervasively present in human cancers. Cancer stem cells (CSCs) play an essential role in metastasis, treatment resistance, and disease recurrence. Therefore, strategies to eradicate CSCs could increase the treatment efficacy and produce more durable clinical remissions in cancer patients. Mitochondrial dynamics is critical for controlling the balance between self-renewal and differentiation of stem cells. Although the underlying molecular mechanisms remain elusive, the link between mitochondria and stemness may provide opportunities for discovering innovative treatment approaches. Here, we provide evidence of a functional link between mitochondria, the Wnt/β-catenin pathway, and the σ1R receptor (σ1R), a unique ligand-activated chaperon protein residing at the endoplasmic reticulum (ER)-mitochondria contact sites. We show that the σ1R/mitochondria/β-catenin axis is crucial for executing the stem cell program and represents a vulnerability in CSCs. Inhibiting σ1R with synthetic antagonists or genetic knockdown disrupts mitochondrial dynamics and Wnt/β-catenin signaling leading to loss of self-renewal and progressive exhaustion of the CSC progeny. Activation of σ1R/mitochondria/β-catenin signaling occurs preferentially in metastatic castration-resistant prostate cancer (CRPC) compared to hormone-naïve primary tumors and is associated with clinical progression. The critical role of σ1R in controlling the tumor-initiating capability of CSCs provides novel avenues for anticancer drug discovery.mamamilan