mTOR inhibition affects Yap1-β-catenin-induced hepatoblastoma growth and development
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Laura Molina1,2,*, Hong Yang3,*, Adeola O. Adebayo Michael4, Michael Oertel1,5, Aaron Bell1, Sucha Singh1, Xin Chen6, Junyan Tao1 and Satdarshan P.S. Monga1,5,7
1Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
2Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
3Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Guangxi, China
4Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA
5Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh PA, USA
6Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
7Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
*These authors have contributed equally to this work
Satdarshan P.S. Monga, email: email@example.com
Junyan Tao, email: firstname.lastname@example.org
Keywords: pediatric liver tumor; Wnt signaling; mTOR pathway; beta-catenin; YAP1
Received: December 20, 2018 Accepted: January 22, 2019 Published: February 19, 2019
Hepatoblastoma (HB) is the most common pediatric liver malignancy. Around 80% of HB demonstrate simultaneous activation of β-catenin and Yes-associated protein 1 (Yap1). The mechanism by which these signaling pathways contribute to HB pathogenesis remain obscure. Recently, mTORC1 activation was reported in human HB cells and in a murine HB model driven by β-catenin and Yap1. Here, we directly investigate the therapeutic impact of mTOR inhibition following HB development in the Yap1-β-catenin model. HB were established by hydrodynamic tail vein injection of Sleeping Beauty transposase and plasmids coding for ΔN90-β-catenin and S127A-Yap1. Five weeks after injection, when HB were evident, mice were randomized into Rapamycin diet-fed or basal-diet-fed groups for 5-weeks. Tumor growth was monitored via ultrasound imaging and mice in both groups were euthanized after 5-weeks for molecular analysis. Transcriptomic analysis showed a strong correlation in gene expression between HB in the Yap1-β-catenin model and HB patient cohorts. Rapamycin treatment decreased HB burden, almost normalizing liver weight to body weight ratio. Ultrasound imaging showed reduction in tumor growth over the duration of Rapamycin treatment as compared to controls. Majority of HB in the controls exhibited crowded fetal or embryonal histology, while remnant tumors in the experimental group showed well-differentiated fetal morphology. Immunohistochemistry confirmed inhibition of mTORC1 in the Rapamycin group. Thus, Rapamycin reduces HB in a clinically relevant model driven by β-catenin and Yap1, supporting use of mTORC1 inhibitors in their therapy. We also show the utility of standard and 3D ultrasound imaging for monitoring liver tumors in mice.
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