Combined systemic disruption of MET and EGFR signaling causes liver failure in normal mice

MET and EGFR receptor tyrosine kinases are crucial for liver regeneration and normal hepatocyte function. Recently we demonstrated that in mice, combined inhibition of these two signaling pathways abolished liver regeneration following hepatectomy, with subsequent hepatic failure and death at 15-18 days post-resection. Morbidity was associated with distinct and specific alterations in important downstream signaling pathways that led to a decrease in hepatocyte volume, reduced proliferation, and shutdown of many essential hepatocyte functions such as fatty acid synthesis, urea cycle, and mitochondrial functions. In the present study we explore the role of MET and EGFR signaling in resting mouse livers that are not subjected to hepatectomy. Mice with combined disruption of MET and EGFR signaling (Delta MET + EGFRi) were noticeably sick by 10 day and died at 12-14 days. Delta MET + EGFRi mice showed decreased liver to body weight ratios, increased apoptosis in non-parenchymal cells, impaired liver metabolic functions, and activation of distinct, downstream signaling pathways related to inflammation, cell death, and survival. Conclusion: The present study demonstrates that in addition to controlling the regenerative response, MET and EGFR synergistically control baseline liver homeostasis in normal mice in such a way that their combined disruption leads to liver failure and death. We used microarrays to detail the global programme of gene expression in Delta MET + EGFRi mice liver vs control mice liver Systemic disruption of MET-EGFR signaling pathway in mice was carried out by using a tamoxifen inducible system to systemically delete exon 16 of MET; EGFR was inhibited by using Canertinib added to diet begining 4-day after tamoxifen clearence. Animals were sacrificed at 7 and 10 days after start of Canertinib diet. Controls were administered corn oil (control vehicle, no Tamoxifen). To remain consistent, we also allowed these animals a 4-day resting period, and then harvested their livers 7 and 10 days later.