Civenni Gianluca, Sandrini Giada, Merulla Jessica, Musumeci Carola, Federici Elisa, Vallegra Arianna, Kokanovic Aleksandra, Mosole Simone, Shinde Dheeraj, Sorrenti Elisa, Paganoni Alyssa J J, Marchetti Martina, Valzelli Riccardo, Albino Domenico, Pecoraro Matteo, Rinaldi Andrea, Bolis Marco, Geiger Roger, Winge Tobias, Holtschulte Catharina, Laurini Erik, Pricl Sabrina, Carbone Giuseppina M, Wünsch Bernhard, Catapano Carlo V
Institute of Oncology Research (IOR), Università della Svizzera italiana (USI), Bellinzona, Switzerland.
Bioinformatics Core Unit, Institute of Oncology Research (IOR) and Swiss Institute of Bioinformatics, Bellinzona, Switzerland.
Oncogene. 2025 Sep 2. doi: 10.1038/s41388-025-03541-7.
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 σ receptor (σR), 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 σR controls CSC self-renewal capacity and tumorigenic proficiency by coordinating mitochondrial dynamics and mitochondrial-nuclear signaling. Inhibiting σR with synthetic antagonists and RNA interference led to the progressive exhaustion and loss of tumorigenicity of the CSC progeny. Mechanistically, interfering with σR function disrupted mitochondria homeostasis and triggered β-catenin degradation. Examining clinical CRPC samples, we found a tight correlation between σR and mitochondrial gene expression. Furthermore, σR and β-catenin protein levels were highly correlated in prostate tumors with significant upregulation in metastatic CRPCs, sustaining a role of the σR-mitochondria-β-catenin axis in disease progression. This σR-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.
癌症干细胞（CSCs）普遍存在于人类癌症中，在治疗失败和疾病复发中起着根本性作用。确定维持CSC表型的关键因素可能会带来新的癌症治疗策略。在这里，我们提供了证据，表明σ受体（σR）（一种优先驻留在内质网 - 线粒体接触位点的配体调节伴侣蛋白）与去势抵抗性前列腺癌（CRPCs）中的CSCs之间存在重要联系。通过将多种临床前模型中的功能测定与转录组学和蛋白质组学数据相结合，我们发现σR通过协调线粒体动力学和线粒体 - 核信号传导来控制CSC的自我更新能力和致瘤能力。用合成拮抗剂和RNA干扰抑制σR会导致CSC后代逐渐耗尽并丧失致瘤性。从机制上讲，干扰σR功能会破坏线粒体稳态并触发β - 连环蛋白降解。检查临床CRPC样本时，我们发现σR与线粒体基因表达之间存在紧密相关性。此外，在前列腺肿瘤中，σR和β - 连环蛋白的蛋白质水平高度相关，在转移性CRPC中显著上调，这支持了σR - 线粒体 - β - 连环蛋白轴在疾病进展中的作用。这个以σR为中心的轴对于维持CSC的自我更新和致瘤能力至关重要，并且代表了一个可用于发现新型CSC导向疗法的关键弱点。
