细胞外基质
类有机物
间质细胞
外体
肿瘤微环境
赖氨酰氧化酶
胰腺癌
微泡
癌相关成纤维细胞
癌症研究
细胞生物学
结缔组织增生
癌症
癌细胞
生物
化学
医学
小RNA
内科学
生物化学
肿瘤细胞
基因
遗传学
作者
Weikun Xiao,Mahsa Pahlavanneshan,Chae-Young Eun,Xinyu Zhang,Charlene DeKalb,Bayan Mahgoub,Hanaa Knaneh-Monem,Syed Niaz Ali Shah,Alireza Sohrabi,Stephanie K. Seidlits,Reuben Hill
标识
DOI:10.1016/j.mbplus.2022.100111
摘要
In pancreatic ductal adenocarcinoma (PDAC), the abundant stromal cells which comprise the tumor microenvironment constitute more than 90% of the primary tumor bulk. Moreover, this desmoplastic environment has been found to be three times stiffer than normal pancreas tissue. Despite the importance of studying the desmoplastic environment of PDAC, there is still a lack of models designed to adequately recapitulate this complex stiff microenvironment, a critical hallmark of the disease that has been shown to induce chemoresistance. Here, we present a bio-mimetic, 3-dimensional co-culture system that integrates tumor organoids and host-matching stromal cancer associated-fibroblasts (CAFs) that recapitulates the complex, fibrotic matrix of PDAC using advanced biomaterials. With this model, we show that matrix-activated CAFs are able to “re-engineer” the fibrotic environment into a significantly stiffer environment through lysyl-oxidase dependent crosslinking. Moreover, we show that culture of CAFs in this model leads to an increase of exosomes; extracellular vesicles known to promote chemoresistance. Finally, using previously identified exosome inhibitors, climbazole and imipramine, we demonstrate how abrogation of exosome hypersecretion can reduce matrix stiffness-induced chemoresistance. These data highlight the importance of the development of new models that recapitulate not only the cellular composition found in PDAC tumors, but also the biophysical stresses, like stiffness, that the cells are exposed to in order to identify therapies that can overcome this critical feature which can contribute to the chemoresistance observed in patients. We believe that the 3D bio-mimetic model we have developed will be a valuable tool for the development, testing, and optimization of “mechano-medicines” designed to target the biophysical forces that lead to tumor growth and chemoresistance.
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