Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=41319192&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Stiffness-Tunable Hydrogel Microfluidic Chip Reveals the Role of Stiffness in Cholangiocarcinoma Invasion and Pre-Metastatic Niche Formation #MMPMID41319192
Wu L; Wu G; Wu D; Hu W; Du Q; Lu Q; Wang J; Xie A; Yang Y; Liu J; Zhang W; Sun C; Hu B; Yao Z; Deng H; Xia M; Hu H; Wang S
Adv Healthc Mater 2025[Nov]; ? (?): e03515 PMID41319192show ga
Cholangiocarcinoma (CCA), particularly intrahepatic cholangiocarcinoma (ICC), is a highly aggressive malignancy with extensive stromal fibrosis and frequent pulmonary metastasis. Existing in vitro models, including 2D cultures, animal systems, and Matrigel-based organoids with fixed stiffness, fail to replicate physiologically relevant cell-matrix interactions. Here, we developed a stiffness-tunable microfluidic chip integrating sodium alginate-decellularized ECM (SA-dECM) hydrogels, enabling dynamic modulation of stiffness (2.90-13.31 kPa) to mimic clinical tumor conditions ( approximately 7.94 kPa). Increased stiffness promotes chemoresistance, with gemcitabine IC(50) rising from 0.139 to 0.282 microm and cisplatin from 2.49 to 4.23 microm, alongside epithelial-mesenchymal transition (EMT), as evidenced by a 64% reduction in E-cadherin and a 6.35 fold increase in MMP2 expression. Co-culture of ICC organoids and lung fibroblasts on-chip further reveals that stiff matrices activate fibroblasts via TGF-beta signaling, increasing alpha-SMA and collagen deposition by 7.5 and 5.4 fold, respectively. These changes contribute to a pre-metastatic niche, as confirmed by a 4.11 fold increase in invasive cell counts in PET membrane invasion assays. This dynamic stiffness-tunable platform provides a robust in vitro model for studying stiffness-driven invasion and pre-metastatic niche formation in ICC and offers a valuable tool for personalized screening of anti-fibrotic and chemosensitizing therapies.
Adv+Healthc+Mater 2025 ; ? (?): e03515
