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mTOR Inhibition Delays Hepatoblastoma Growth in a Relevant Mouse Model
Author(s) -
Monga Satdarshan Pal,
Molina Laura Maria,
Yang Hong,
Adebayo Michael Adeola O.,
Tao Junyan,
Bell Aaron
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.662.66
Subject(s) - hepatoblastoma , pi3k/akt/mtor pathway , mtorc1 , cancer research , wnt signaling pathway , ribosomal protein s6 , yap1 , chemistry , medicine , p70 s6 kinase 1 , biology , signal transduction , microbiology and biotechnology , transcription factor , gene , biochemistry
Hepatoblastoma (HB) is the most common pediatric liver malignancy, affecting children in their first few years of life. Around 80% of HB demonstrate simultaneous activation of β‐catenin and Yes‐associated protein 1 (YAP1), which are transcriptional coactivators downstream of the Wnt and Hippo signaling pathways, respectively. Recently, mTORC1 activation was reported in human HB cell lines as well as HB tumors in a mouse model driven by β‐catenin and YAP1. In the current study we investigated directly the impact of mTOR inhibition on HB development in a YAP1‐β‐catenin HB mouse model. Hydrodynamic tail vein injection (HTVI) was used to co‐deliver Sleeping Beauty transposase along with plasmids coding for ΔN90‐β‐catenin and S127A‐YAP1. Five weeks post‐HTVI, when HB tumors are evident, we treated half of the mice with rapamycin via diet, and both control and treated groups were monitored with ultrasound imaging to assess tumor growth over time. All mice were sacrificed at 10 weeks post‐HTVI. Our results show that mice treated with rapamycin for 5 weeks developed significantly less HB tumor burden than control mice, with almost normal liver weight to body weight ratio and fewer, smaller tumors observed histologically. We show by immunohistochemistry that rapamycin treatment reduces activation of downstream targets of mTORC1 signaling such as phosphorylation of 4EBP1 and S6‐ribosomal protein. Importantly, we show by ultrasound imaging that control mice exhibit a dramatic rise in tumor number and volume starting at ~5 weeks post‐HTVI, while rapamycin‐treated mice begin to show a similar increase only at 8–9 weeks post‐HTVI (after 3–4 weeks of rapamycin treatment). Interestingly, while a majority of HB tumors in the control group exhibit embryonal histology, the tumors that developed in rapamycin‐treated mice exhibit more well differentiated, fetal histology. Thus we show that while rapamycin does not completely block HB tumor formation, it significantly delays the development of tumors driven by β‐catenin and YAP1. Our study also demonstrates the utility of standard and 3D ultrasound imaging for the monitoring of liver tumor formation in mice and supports the use of mTORC1 inhibitors for HB treatment. Support or Funding Information This work was supported by NIH grants 1R01DK62277, 1R01DK100287, 1R01CA204586, and the Endowed Chair for Experimental Pathology (S.P.M.), as well as CATER T32 grant 5T32EB001026‐14 (L.M.). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .