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矩阵刚度会影响大脑转移性乳腺癌细胞对化疗和向治疗的反应

Venu Yakati¹, Lalita A Shevde², Shreyas S Rao¹

¹Department of Chemical and Biological Engineering, The University of Alabama, Tuscaloosa, AL 35487, USA. srao3@eng.ua.edu.

Biomaterials science

|June 24, 2024

概括

矩阵刚度影响乳腺癌脑转移休眠和耐药性. 软矩阵通过p38/SGK1通路促进休眠和抵抗,而硬矩阵提高药物反应能力.

科学领域:

在瘤学瘤学.
生物材料科学生物材料科学
细胞生物学细胞生物学

背景情况:

乳腺癌经常转移到大脑,细胞可以进入休眠状态.
休眠的癌细胞表现出对治疗的耐药性,这是大脑转移性乳腺癌 (BMBC) 鲜为人知的机制.
了解休眠驱动的治疗阻力对于改善BMBC患者的治疗结果至关重要.

研究的目的:

调查矩阵刚度在调节休眠细胞与增殖性BMBC细胞药物反应中的作用.
阐明BMBC中休眠相关的治疗阻力背后的分子机制.
探索针对BMBC休眠期的潜在治疗策略.

主要方法:

使用不同硬度 (软度~0.4kPa,硬度~4.5kPa) 的氨酸 (HA) 水凝培养BMBC细胞.
在休眠 (软HA) 和增殖 (硬HA) 细胞中评估药物反应 (Paclitaxel,Lapatinib).
研究了血清/葡萄糖皮质体调节激酶1 (SGK1) 基因和p38信号通路在休眠相关抗性的参与.

主要成果:

软HA水凝 (休眠表型) 上的细胞对帕克利塔塞尔和拉帕提尼布产生了耐药性.
硬HA水凝 (增殖表型) 上的细胞对帕克利塔克塞尔和拉帕提尼布有反应.
与休眠相关的耐药性与SGK1基因上调相关,部分由p38信号通路介导.
抑制SGK1诱导了休眠转变为繁殖的开关,并恢复了治疗灵敏度.

结论:

矩阵刚度显著影响休眠与增殖的BMBC细胞的治疗反应.
p38/SGK1信号轴在调解休眠相关药物耐药性方面发挥着关键作用.
准SGK1可能提供一种策略,以克服休眠大脑转移性乳腺癌中治疗阻力.

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