ArticleJournal of experimental & clinical cancer research : CR2024
Targeting cancer-associated fibroblasts/tumor cells cross-talk inhibits intrahepatic cholangiocarcinoma progression via cell-cycle arrest.
Article in Journal of experimental & clinical cancer research : CR, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Fibroblast-associated TPM2 links cell-matrix remodeling to EMT-Notch signaling and gemcitabine resistance in intrahepatic cholangiocarcinoma.Cancer biology & therapy · 2026Article
- Therapeutic targeting of cancer-associated fibroblasts with oncolytic virus in preclinical models of intrahepatic cholangiocarcinoma.Molecular therapy. Oncology · 2026Article
- In Vitro Radiobiological Evaluation of [Pharmaceuticals (Basel, Switzerland) · 2026Article
- Integrated analysis reveals survival-related genes promoting cholangiocarcinoma progression via G2/M cell cycle, with validation of cyclin B1 in tumor proliferation.Scientific reports · 2025Article
- The DNA Minor Groove Binders Trabectedin and Lurbinectedin Are Potent Antitumor Agents in Human Intrahepatic Cholangiocarcinoma.International journal of molecular sciences · 2025Article
- Metabolic collusion driving immune evasion in cholangiocarcinoma: unmasking the dual control of the immuno-metabolic microenvironment.Frontiers in immunology · 2025Review
- Revisiting the role of cancer-associated fibroblasts in tumor microenvironment.Frontiers in immunology · 2025Review
- Applications of 3D models in cholangiocarcinoma.Frontiers in oncology · 2025Review
- Integrated transcriptomic analysis identifies lactylation-linked gemcitabine resistance and therapeutic targets in intrahepatic cholangiocarcinoma.Frontiers in cell and developmental biology · 2025Article
- Organoids and spheroids: advancedFrontiers in cell and developmental biology · 2024Review
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Authors and funding
12 authors.
Funding
Abstract
backgroundCancer-associated fibroblasts (CAFs), mainly responsible for the desmoplastic reaction hallmark of intrahepatic Cholangiocarcinoma (iCCA), likely have a role in tumor aggressiveness and resistance to therapy, although the molecular mechanisms involved are unknown. Aim of the study is to investigate how targeting hCAF/iCCA cross-talk with a Notch1 inhibitor, namely Crenigacestat, may affect cancer progression.
methodsWe used different in vitro models in 2D and established new 3D hetero-spheroids with iCCA cells and human (h)CAFs. The results were confirmed in a xenograft model, and explanted tumoral tissues underwent transcriptomic and bioinformatic analysis.
resultshCAFs/iCCA cross-talk sustains increased migration of both KKU-M213 and KKU-M156 cells, while Crenigacestat significantly inhibits only the cross-talk stimulated migration. Hetero-spheroids grew larger than homo-spheroids, formed by only iCCA cells. Crenigacestat significantly reduced the invasion and growth of hetero- but not of homo-spheroids. In xenograft models, hCAFs/KKU-M213 tumors grew significantly larger than KKU-M213 tumors, but were significantly reduced in volume by Crenigacestat treatment, which also significantly decreased the fibrotic reaction. Ingenuity pathway analysis revealed that genes of hCAFs/KKU-M213 but not of KKU-M213 tumors increased tumor lesions, and that Crenigacestat treatment inhibited the modulated canonical pathways. Cell cycle checkpoints were the most notably modulated pathway and Crenigacestat reduced CCNE2 gene expression, consequently inducing cell cycle arrest. In hetero-spheroids, the number of cells increased in the G2/M cell cycle phase, while Crenigacestat significantly decreased cell numbers in the G2/M phase in hetero but not in homo-spheroids.
conclusionsThe hCAFs/iCCA cross-talk is a new target for reducing cancer progression with drugs such as Crenigacestat.
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