Focal adhesion kinase (FAK) promotes cholangiocarcinoma development and progression via YAP activation

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

doi:10.1016/j.jhep.2021.05.018

Focal adhesion kinase (FAK) promotes cholangiocarcinoma development and progression via YAP activation

J Hepatol. 2021 Oct;75(4):888-899. doi: 10.1016/j.jhep.2021.05.018. Epub 2021 May 28.

Authors

Xinhua Song¹, Hongwei Xu², Pan Wang³, Jingxiao Wang⁴, Silvia Affo⁵, Haichuan Wang², Meng Xu⁶, Binyong Liang⁷, Li Che⁸, Wei Qiu⁹, Robert F Schwabe⁵, Tammy T Chang¹⁰, Marion Vogl¹¹, Giovanni M Pes¹², Silvia Ribback¹³, Matthias Evert¹¹, Xin Chen¹⁴, Diego F Calvisi¹⁵

Affiliations

¹ Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA. Electronic address: songxinhua0726@yeah.net.
² Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA; Liver Transplantation Division, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China; Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
³ Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA; Collaborative Innovation Center for Agricultural Product Processing and Nutrition & Health, Beijing Vegetable Research Center, Beijing Academy of Agriculture 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'an Jiaotong University, Xi'an Jiaotong University, Xi'an, PR China.
⁷ Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁸ Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
⁹ Department of Surgery and Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA.
¹⁰ Department of Surgery and Liver Center, University of California, San Francisco, CA, USA.
¹¹ Institute of Pathology, University of Regensburg, Regensburg, Germany.
¹² Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Sassari, Italy.
¹³ Institute of Pathology, University of Greifswald, Greifswald, Germany.
¹⁴ Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA. Electronic address: xin.chen@ucsf.edu.
¹⁵ Institute of Pathology, University of Regensburg, Regensburg, Germany. Electronic address: diego.calvisi@klinik.uni-regensburg.de.

Abstract

Background & aims: Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is upregulated in many tumor types and is a promising target for cancer therapy. Herein, we elucidated the functional role of FAK in intrahepatic cholangiocarcinoma (iCCA) development and progression.

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: We found that the protein FAK (focal adhesion kinase) is upregulated and activated in human and mouse intrahepatic cholangiocarcinoma samples. FAK promotes intrahepatic cholangiocarcinoma development, whereas deletion of FAK strongly suppresses its initiation and progression. Combined FAK and CDK4/6 inhibitor treatment had a strong anti-cancer effect in in vitro and in vivo models. This combination therapy might represent a valuable and novel treatment against human intrahepatic cholangiocarcinoma.

Keywords: FAK; YAP; cancer; intrahepatic cholangiocarcinoma; targeted therapy.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
California
Cholangiocarcinoma / etiology
Cohort Studies
Disease Models, Animal
Focal Adhesion Protein-Tyrosine Kinases / administration & dosage
Focal Adhesion Protein-Tyrosine Kinases / adverse effects*
Mice
Signal Transduction / drug effects
YAP-Signaling Proteins / administration & dosage
YAP-Signaling Proteins / drug effects*

Substances

YAP-Signaling Proteins
Focal Adhesion Protein-Tyrosine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding