Abstract | BACKGROUND & AIMS: METHODS: Expression levels and activation status of FAK were determined in human iCCA samples. The functional contribution of FAK to Akt/YAP murine iCCA initiation and progression was investigated using conditional Fak knockout mice and constitutive Cre or inducible Cre mice, respectively. The oncogenic potential of FAK was further examined via overexpression of FAK in mice. In vitro cell line studies and in vivo drug treatment were applied to address the therapeutic potential of targeting FAK for iCCA treatment. RESULTS: FAK was ubiquitously upregulated and activated in iCCA lesions. Ablation of FAK strongly delayed Akt/YAP-driven mouse iCCA initiation. FAK overexpression synergized with activated AKT to promote iCCA development and accelerated Akt/Jag1-driven cholangiocarcinogenesis. Mechanistically, FAK was required for YAP(Y357) phosphorylation, supporting the role of FAK as a central YAP regulator in iCCA. Significantly, ablation of FAK after Akt/YAP-dependent iCCA formation strongly suppressed tumor progression in mice. Furthermore, a remarkable iCCA growth reduction was achieved when a FAK inhibitor and palbociclib, a CDK4/6 inhibitor, were administered simultaneously in human iCCA cell lines and Akt/YAP mice. CONCLUSIONS: FAK activation contributes to the initiation and progression of iCCA by inducing the YAP proto-oncogene. Targeting FAK, either alone or in combination with anti-CDK4/6 inhibitors, may be an effective strategy for iCCA treatment. LAY SUMMARY:
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Authors | Xinhua Song, Hongwei Xu, Pan Wang, Jingxiao Wang, Silvia Affo, Haichuan Wang, Meng Xu, Binyong Liang, Li Che, Wei Qiu, Robert F Schwabe, Tammy T Chang, Marion Vogl, Giovanni M Pes, Silvia Ribback, Matthias Evert, Xin Chen, Diego F Calvisi |
Journal | Journal of hepatology
(J Hepatol)
Vol. 75
Issue 4
Pg. 888-899
(10 2021)
ISSN: 1600-0641 [Electronic] Netherlands |
PMID | 34052254
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. |
Chemical References |
- YAP-Signaling Proteins
- Focal Adhesion Protein-Tyrosine Kinases
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Topics |
- Animals
- California
- Cholangiocarcinoma
(etiology)
- Cohort Studies
- Disease Models, Animal
- Focal Adhesion Protein-Tyrosine Kinases
(administration & dosage, adverse effects)
- Mice
- Signal Transduction
(drug effects)
- YAP-Signaling Proteins
(administration & dosage, drug effects)
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