Franciosa Giulia, Nieddu Valentina, Battistini Chiara, Caffarini Miriam, Lupia Michela, Colombo Nicoletta, Fusco Nicola, Olsen Jesper V, Cavallaro Ugo
Novo Nordisk Foundation Center for Protein Research, Department of Cellular andMolecular Medicine, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark.
Unit of Gynecological Oncology Research, European Institute of Oncology IRCSS, Milano, Italy.
Mol Cell Proteomics. 2025 May;24(5):100965. doi: 10.1016/j.mcpro.2025.100965. Epub 2025 Apr 7.
High-grade serous ovarian carcinoma (HGSOC) is the deadliest gynecologic cancer. Key to the progression and ultimate lethality of this subtype is the intra-tumoral heterogeneity, which is defined as the coexistence of different cell types and populations within a single tumor. Among those, ovarian cancer stem cells (OCSCs) are a distinct subpopulation of tumor cells endowed with stem-like properties, which can survive current standard therapies, resulting in tumor recurrence. Here, we generated ex vivo primary OCSC-enriched three-dimensional (3D) spheres from 10 distinct treatment naive patient-derived adherent (2D) cultures. We used state-of-the-art quantitative mass spectrometry to characterize the molecular events associated with OCSCs by analyzing their proteome and phosphoproteome. Our data revealed a stemness-related protein signature, shared within a heterogeneous patient cohort, which correlates with chemo-refractoriness in a clinical proteomics dataset. Moreover, we identified targetable deregulated kinases and aberrant PDGF receptor activation in OCSCs. Pharmacological inhibition of PDGFR in adherent OC cells reduced the stemness potential, measured by sphere formation assay. Overall, we provide a valuable resource to identify new OCSC markers and putative targets for OCSC-directed therapies.
高级别浆液性卵巢癌（HGSOC）是最致命的妇科癌症。这种亚型进展和最终致死的关键在于肿瘤内异质性，即单个肿瘤内不同细胞类型和群体的共存。其中，卵巢癌干细胞（OCSCs）是具有干细胞样特性的独特肿瘤细胞亚群，能够在当前标准治疗中存活，导致肿瘤复发。在此，我们从10种不同的未经治疗的患者来源的贴壁（二维）培养物中体外生成了富含原代OCSCs的三维（3D）球体。我们使用最先进的定量质谱技术，通过分析其蛋白质组和磷酸化蛋白质组来表征与OCSCs相关的分子事件。我们的数据揭示了一种在异质性患者队列中共享的干性相关蛋白质特征，该特征与临床蛋白质组学数据集中的化疗难治性相关。此外，我们在OCSCs中鉴定出可靶向的失调激酶和异常的血小板衍生生长因子受体（PDGF受体）激活。对贴壁OC细胞中PDGFR的药理学抑制降低了通过球体形成试验测量的干性潜能。总体而言，我们提供了一个宝贵的资源，用于鉴定新的OCSC标志物和OCSC定向治疗的潜在靶点。
