Research Papers:

YAP-associated chromosomal instability and cholangiocarcinoma in mice

Sumera Rizvi, Samantha R. Fischbach, Steven F. Bronk, Petra Hirsova, Anuradha Krishnan, Renumathy Dhanasekaran, James B. Smadbeck, Rory L. Smoot, George Vasmatzis and Gregory J. Gores _

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Oncotarget. 2018; 9:5892-5905. https://doi.org/10.18632/oncotarget.23638

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Sumera Rizvi1, Samantha R. Fischbach1, Steven F. Bronk1, Petra Hirsova1,2,3, Anuradha Krishnan1, Renumathy Dhanasekaran4, James B. Smadbeck5, Rory L. Smoot6, George Vasmatzis5 and Gregory J. Gores1

1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, 55905 MN, USA

2Institute of Clinical Biochemistry and Diagnostics, Charles University, Faculty of Medicine and University Hospital Hradec Kralove, Hradec Kralove 500 05, Czech Republic

3Department of Pharmacology, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove 500 03, Czech Republic

4Division of Gastroenterology and Hepatology, Stanford University, Stanford, 94304 CA, USA

5Department of Biomarker Discovery, Center for Individualized Medicine, Mayo Clinic, Rochester, 55905 MN, USA

6Department of Surgery, Mayo Clinic, Rochester, 55905 MN, USA

Correspondence to:

Gregory J. Gores, email: [email protected]

Keywords: chromosomal instability; FOXM1; mate-pair sequencing; SB cell lines

Received: September 30, 2017     Accepted: December 08, 2017     Published: December 22, 2017


Deregulated Hippo pathway signaling is associated with aberrant activation of the downstream effector yes-associated protein (YAP), an emerging key oncogenic mediator in cholangiocarcinoma (CCA). In our prior work, we have demonstrated that biliary transduction of YAP along with Akt as a permissive factor induces CCA in mice. To further delineate the mechanisms associated with YAP-associated biliary oncogenesis, we have established seven malignant murine cell lines from our YAP-driven murine CCA model. These cells express the CCA markers SRY (Sex Determining Region Y)-Box 9 (SOX9), cytokeratin (CK)-7 and 19 but lack hepatocyte nuclear factor 4 alpha and alpha-smooth muscle actin, markers of hepatocellular carcinoma and cancer-associated fibroblasts, respectively. Notably, the murine CCA cells can be readily implanted into mouse livers with resultant orthotopic tumor formation. In this unique syngeneic orthotopic murine model, tumors exhibit histopathologic features resembling human CCA. We analyzed transcriptome data from YAP-associated parent CCA tumor nodules and identified a gene expression pattern associated with chromosomal instability, known as CIN25. Similarly, mate-pair sequencing of the murine CCA cells revealed chromosomal missegregation with gains and losses of several whole chromosomes demonstrating aneuploidy. Of the CIN25 genes, forkhead box M1 (Foxm1), a key cell cycle regulator, was the most significantly upregulated CIN25 gene product. Accordingly, small interfering RNA (siRNA)-mediated silencing of YAP as well as FOXM1 inhibition with thiostrepton induced CCA cell death. These preclinical data imply a role for YAP-mediated chromosomal instability in cholangiocarcinoma, and suggest FOXM1 inhibition as a therapeutic target for CCA.

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