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Focal Adhesion Kinase (FAK) promotes cholangiocarcinoma development and progression via YAP activation.

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机构： [1]Department of Bioengineering and Therapeutic Sciences and Liver Center,University of California, San Francisco, CA, USA [2]Liver Transplantation Division, Department of Liver Surgery, West ChinaHospital, Sichuan University, Chengdu, China, Laboratory of Liver Surgery,West China Hospital, Sichuan University, Chengdu, Sichuan, People'sRepublic of China [3]Collaborative Innovation Center for Agricultural Product Processing andNutrition & Health, Beijing Vegetable Research Center, Beijing Academy ofAgriculture and Forestry Science, Beijing, China [4]Beijing University of Chinese Medicine, Beijing, China [5]Department of Medicine, Columbia University, New York, NY, USA [6]Department of General Surgery, The Second Affiliated Hospital of Xi'anJiaotong University, Xi'an Jiaotong University, Xi'an, PR China [7]Hepatic Surgery Center, Department of Surgery, Tongji Hospital, TongjiMedical College, Huazhong University of Science and Technology, Wuhan China [8]Department of Surgery and Cancer Biology, Loyola University Chicago StritchSchool of Medicine, Maywood, IL [9]Department of Surgery and Liver Center, University of California, SanFrancisco, CA, USA [10]Institute of Pathology, University of Regensburg, Regensburg, Germany [11]Department of Medical, Surgical, and Experimental Sciences, University ofSassari, Sassari, Italy [12]Institute of Pathology, University of Greifswald, Greifswald, Germany [13]R&D Center, Legend Biotech USA Inc, Piscataway, NewJersey, USA

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Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase upregulated in many tumor types and a promising target for cancer therapy. Here, we elucidated the functional role of FAK in intrahepatic cholangiocarcinoma (iCCA) development and progression.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 KO 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.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.FAK activation contributes to the initiation and progression of iCCA by inducing the YAP protooncogene. Targeting FAK, either alone or in combination with anti-CDK4/6 inhibitors, may be an effective strategy for iCCA treatment.We found that Focal Adhesion Kinase (FAK) is upregulated and activated in human and mouse intrahepatic cholangiocarcinoma (iCCA) samples. FAK promotes iCCA development, whereas deletion of FAK strongly suppresses iCCA initiation and progression. Mechanistically, we discovered that FAK regulates the YAP pathway. Combined FAK and CDK4/6 inhibitor treatment is highly detrimental for the growth of in vitro and in vivo iCCA models. This combination therapy might represent a valuable and novel treatment against human iCCA.Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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大类 | 1 区

医学

小类 | 1 区胃肠肝病学

最新[2023]版：

大类 | 1 区

医学

小类 | 1 区胃肠肝病学

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出版当年[2021]版：

Q1 GASTROENTEROLOGY & HEPATOLOGY

最新[2023]版：

Q1 GASTROENTEROLOGY & HEPATOLOGY

影响因子： 26.8 最新[2023版] 28 最新五年平均 30.083 出版当年[2021版] 27.385 出版当年五年平均 25.083 出版前一年[2020版] 25.7 出版后一年[2022版]

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第一作者机构： [1]Department of Bioengineering and Therapeutic Sciences and Liver Center,University of California, San Francisco, CA, USA

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通讯机构： [1]Department of Bioengineering and Therapeutic Sciences and Liver Center,University of California, San Francisco, CA, USA [10]Institute of Pathology, University of Regensburg, Regensburg, Germany [*1]Institute of Pathology, University of Regensburg, Franz-Joseph-Strauss Allee 11, 93053 Regensburg, Germany [*2]UCSF, 513 Parnassus Avenue, San Francisco, CA 94143, USA

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