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Author Spotlight: Investigating Liver Cancer Pathogenesis Using Patient-Derived Organoids
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Author Spotlight: Investigating Liver Cancer Pathogenesis Using Patient-Derived Organoids

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Targeting mTOR and Src restricts hepatocellular carcinoma growth in a novel murine liver cancer model

Sarah Walker1,2, Miriam Wankell3, Vikki Ho1

  • 1Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, Australia.

Plos One
|February 23, 2019
PubMed

Insights

Adiponectin deficiency exacerbates liver cancer (hepatocellular carcinoma) growth. Combining mTOR and Src inhibitors significantly reduced tumor growth, suggesting a novel therapeutic strategy for hepatocellular carcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Hepatocellular carcinoma (HCC) presents a poor prognosis with limited therapeutic options.
  • Adiponectin (APN) plays a role in regulating cell growth and metabolism.
  • Investigating the role of APN in HCC development and identifying novel therapeutic targets is crucial.

Purpose of the Study:

  • To investigate the impact of adiponectin deficiency on hepatocellular carcinoma (HCC) development and progression.
  • To identify potential therapeutic targets for HCC by analyzing activated signaling pathways.
  • To evaluate the efficacy of combined inhibition of mTOR and Src pathways in HCC treatment.

Main Methods:

  • Generated hepatocellular carcinoma (HCC) cells from adiponectin (APN) knock-out and wild-type murine models.
  • Administered carcinogen diethylnitrosamine to induce tumors.
  • Evaluated tumor growth characteristics in vitro and in vivo.
  • Assessed the activity of mammalian target of Rapamycin (mTOR) and Src pathways.
  • Conducted combinatorial treatment with mTOR inhibitor Rapamycin and Src inhibitor Dasatinib.

Main Results:

  • Adiponectin knock-out mice developed significantly larger tumors (7-fold) compared to wild-type controls.
  • Derived A52 HCC cells from APN KO mice exhibited robust in vitro and in vivo growth with similar pathology to parental tumors.
  • Both primary tumors and cell lines showed activation of mammalian target of Rapamycin (mTOR) and Src pathways.
  • Combined treatment with Rapamycin and Dasatinib reduced A52 HCC growth by 29-fold in vivo.
  • Protein and histological analyses confirmed mTOR and Src pathway activation in human HCC samples.

Conclusions:

  • Adiponectin deficiency promotes hepatocellular carcinoma (HCC) growth.
  • The mammalian target of Rapamycin (mTOR) and Src pathways are activated in HCC.
  • Combined inhibition of mTOR and Src represents a promising novel therapeutic strategy for treating HCC.

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