Abstract
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.
Highlights
Hepatoblastoma (HB) is the most common pediatric liver cancer and is commonly diagnosed in the first few years of life [1]
We show that our murine model of HB using SB-hydrodynamic tail vein injection (HTVI) delivery of mutant Yes-associated protein 1 (Yap1) and β-catenin shows a strong correlation in gene expression patterns with two independent patient HB cohorts, and shows an enrichment in genes associated with less well-differentiated, more proliferative HB
We show that Rapamycin treatment reduced HB and overall tumor burden in the Yap1-β-catenin model by dramatically affecting their growth supporting the its relevance in the therapy for this tumor type
Summary
Hepatoblastoma (HB) is the most common pediatric liver cancer and is commonly diagnosed in the first few years of life [1]. Despite being a rare cancer, the annual incidence of HB has gradually increased over the past three decades [2]. Most cases of HB appear to be sporadic, but some are associated with genetic abnormalities and malformations, such as in cases with BeckwithWiedemann syndrome and familial adenomatous polyposis [3, 4]. Surgical resection along with chemotherapy remains the curative strategy for HB and offers the only realistic chance of long-term disease-free survival [6]. Investigating the genetic and molecular origins of HB will provide better understanding of the disease and identify novel therapeutic approaches
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call