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Upregulation of PD-L1 expression in breast cancer cells through the formation of 3D multicellular cancer aggregates under different chemical and mechanical conditions.
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ( IF 5.1 ) Pub Date : 2019-08-06 , DOI: 10.1016/j.bbamcr.2019.118526
Shohreh Azadi 1 , Hamidreza Aboulkheyr Es 2 , Sajad Razavi Bazaz 2 , Jean Paul Thiery 3 , Mohsen Asadnia 4 , Majid Ebrahimi Warkiani 5
Affiliation  

Expression of programmed death-ligand 1 (PD-L1) in cancer cells plays an important role in cancer-immune cell interaction. The emerging evidence suggests regulation of PD-L1 expression by several tumor microenvironmental cues. However, the association of PD-L1 expression with chemical and mechanical features of the tumor microenvironment, specifically epidermal growth factor receptor (EGFR) signaling and matrix stiffness, remains elusive. Herein, we determine whether EGFR targeting and substrate stiffness affect the regulation of PD-L1 expression. Breast carcinoma cell lines, MCF7 and MDA-MB-231, were cultured under different conditions targeting EGFR and exposing cells to distinct substrate stiffness to evaluate PD-L1 expression. Furthermore, the ability to form aggregates in short-term culture of breast carcinoma cells and its effect on expression level of PD-L1 was probed. Our results indicated that PD-L1 expression was altered in response to both EGFR inhibition and substrate stiffness. Additionally, a positive association between the formation of multicellular aggregates and PD-L1 expression was observed. MDA-MB-231 cells expressed the highest PD-L1 level on a stiff substrate, while inhibition of EGFR reduced expression of PD-L1. The results suggested that both physical and chemical features of tumor microenvironment regulate PD-L1 expression through alteration of tumor aggregate formation potential. In line with these results, the in-silico study highlighted a positive correlation between PD-L1 expression, EGFR signaling, epithelial to mesenchymal transition related transcription factors (EMT-TFs) and stemness markers in metastatic breast cancer. These findings improve our understanding of regulation of PD-L1 expression by tumor microenvironment leading to evasion of tumor cells from the immune system.

中文翻译:

通过在不同化学和机械条件下形成3D多细胞癌聚集体,乳腺癌细胞中PD-L1表达的上调。

程序性死亡配体1(PD-L1)在癌细胞中的表达在癌细胞与免疫细胞的相互作用中起着重要的作用。新兴证据表明,PD-L1表达受多种肿瘤微环境提示的调节。但是,PD-L1表达与肿瘤微环境的化学和机械特征,特别是表皮生长因子受体(EGFR)信号传导和基质刚度之间的关联仍然难以捉摸。在本文中,我们确定EGFR靶向和底物刚度是否影响PD-L1表达的调节。在针对EGFR的不同条件下培养乳腺癌细胞系MCF7和MDA-MB-231,并将细胞暴露于不同的底物硬度以评估PD-L1的表达。此外,探讨了乳腺癌细胞在短期培养中形成聚集体的能力及其对PD-L1表达水平的影响。我们的结果表明,PD-L1的表达响应EGFR抑制和底物刚度而改变。另外,观察到多细胞聚集体的形成与PD-L1表达之间的正相关。MDA-MB-231细胞在坚硬的底物上表达最高的PD-L1水平,而对EGFR的抑制则降低了PD-L1的表达。结果表明,肿瘤微环境的物理和化学特征都通过改变肿瘤聚集体形成潜能来调节PD-L1的表达。与这些结果一致,计算机模拟研究强调了PD-L1表达,EGFR信号传导,上皮到间质转化相关转录因子(EMT-TFs)和干性标志物在转移性乳腺癌中的作用。这些发现提高了我们对肿瘤微环境对PD-L1表达调控的理解,导致肿瘤细胞从免疫系统逃逸。
更新日期:2019-08-06
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