Division of Biochemistry, Department of Basic Sciences, Loma Linda University, Loma Linda, CA 92354, USA.
Department of Biology, California State University San Bernardino, San Bernardino, CA 92407, USA.
Int J Mol Sci. 2024 Mar 29;25(7):3843. doi: 10.3390/ijms25073843.
To understand chemoresistance in the context of cancer stem cells (CSC), a cisplatin resistance model was developed using a high-grade serous ovarian cancer patient-derived, cisplatin-sensitive sample, PDX4. As a molecular subtype-specific stem-like cell line, PDX4 was selected for its representative features, including its histopathological and mutation status, and exposed to cisplatin in vitro. In the cisplatin-resistant cells, transcriptomics were carried out, and cell morphology, protein expression, and functional status were characterized. Additionally, potential signaling pathways involved in cisplatin resistance were explored. Our findings reveal the presence of distinct molecular signatures and phenotypic changes in cisplatin-resistant PDX4 compared to their sensitive counterparts. Surprisingly, we observed that chemoresistance was not inherently linked with increased stemness. In fact, although resistant cells expressed a combination of EMT and stemness markers, functional assays revealed that they were less proliferative, migratory, and clonogenic-features indicative of an underlying complex mechanism for cell survival. Furthermore, DNA damage tolerance and cellular stress management pathways were enriched. This novel, syngeneic model provides a valuable platform for investigating the underlying mechanisms of cisplatin resistance in a clinically relevant context, contributing to the development of targeted therapies tailored to combat resistance in stem-like ovarian cancer.
为了在癌症干细胞（CSC）的背景下理解化疗耐药性，我们使用源自高级别浆液性卵巢癌患者的顺铂敏感样本 PDX4 建立了一个顺铂耐药模型。作为一种分子亚型特异性的类干细胞系，PDX4 因其代表性特征被选中，包括其组织病理学和突变状态，并在体外暴露于顺铂。在顺铂耐药细胞中，进行了转录组学研究，并对细胞形态、蛋白表达和功能状态进行了表征。此外，还探讨了涉及顺铂耐药的潜在信号通路。我们的研究结果揭示了与敏感 PDX4 相比，顺铂耐药 PDX4 中存在明显的分子特征和表型变化。令人惊讶的是，我们观察到化疗耐药性与干性增加并不固有相关。实际上，尽管耐药细胞表达了 EMT 和干性标志物的组合，但功能测定显示它们的增殖、迁移和克隆形成能力较低，这表明存在潜在的复杂细胞存活机制。此外，DNA 损伤耐受和细胞应激管理途径得到了富集。这种新型的同源模型为在临床相关背景下研究顺铂耐药的潜在机制提供了有价值的平台，有助于开发针对卵巢癌类干细胞中耐药性的靶向治疗。
