文章：

获得吉西他滨和紫杉醇化疗耐药性的胰腺导管腺癌细胞机械生物学改变

Altered Mechanobiology of PDAC Cells with Acquired Chemoresistance to Gemcitabine and Paclitaxel

原文发布日期：18 November 2024

DOI: 10.3390/cancers16223863

类型: Article

开放获取: 是

英文摘要：

Background: Pancreatic ductal adenocarcinoma acquired resistance to chemotherapy poses a major limitation to patient survival. Despite understanding some biological mechanisms of chemoresistance, much about those mechanisms remains to be uncovered. Mechanobiology, which studies the physical properties of cells, holds promise as a potential target for addressing the challenges of chemoresistance in PDAC. Therefore, we, here in an initial step, assessed the altered mechanobiology of PDAC cells with acquired chemoresistance to gemcitabine and paclitaxel.Methods: Five PDAC cell lines and six stably resistant subclones were assessed for force generation on elastic micropillar arrays. Those measurements of mechanical phenotype were complemented by single-cell motility and invasion in 3D collagen-based matrix assays. Further, the nuclear translocation of Yes-associated protein (YAP), as a measure of active mechanical status, was compared, and biomarkers of the epithelial-to-mesenchymal transition (EMT) were evaluated using RT-qPCR.Results: The PDAC cells with acquired chemoresistance exert higher traction forces than their parental/wild-type (WT) cells. In 2D, single-cell motility was altered for all the chemoresistant cells, with a cell-type specific pattern. In 3D, the spheroids of the chemoresistant PDAC cells were able to invade the matrix and remodel collagen more than their WT clones. However, YAP nuclear translocation and EMT were not significantly altered in relation to changes in other physical parameters.Conclusions: This is the first study to investigate and report on the altered mechanobiological features of PDAC cells that have acquired chemoresistance. A better understanding of mechanical features could help in identifying future targets to overcome chemoresistance in PDAC.

摘要翻译： 

背景：胰腺导管腺癌获得性化疗耐药是限制患者生存的主要因素。尽管对化疗耐药的某些生物学机制已有了解，但这些机制仍有诸多方面尚待揭示。研究细胞物理特性的力学生物学，有望成为解决PDAC化疗耐药挑战的潜在靶点。因此，我们在此项初步研究中，评估了获得吉西他滨和紫杉醇化疗耐药的PDAC细胞的力学生物学改变。 方法：通过弹性微柱阵列评估五种PDAC细胞系和六个稳定耐药亚克隆的力生成能力。这些力学表型测量辅以基于3D胶原基质的单细胞运动性和侵袭性检测。此外，比较了作为机械活性状态指标的Yes相关蛋白（YAP）核转位情况，并采用RT-qPCR评估了上皮-间质转化（EMT）的生物标志物。 结果：获得性化疗耐药的PDAC细胞比其亲代/野生型（WT）细胞产生更高的牵引力。在二维条件下，所有耐药细胞的单细胞运动性均发生改变，且呈现细胞类型特异性模式。在三维环境中，耐药PDAC细胞球体比其WT克隆具有更强的基质侵袭和胶原重塑能力。然而，YAP核转位和EMT并未随其他物理参数的变化而发生显著改变。 结论：本研究首次探讨并报道了获得性化疗耐药的PDAC细胞力学生物学特征的改变。深入理解这些力学特征有助于确定未来克服PDAC化疗耐药的潜在靶点。

原文链接：

Altered Mechanobiology of PDAC Cells with Acquired Chemoresistance to Gemcitabine and Paclitaxel