Pathobiology 2027

Our group has focused on elucidating the many roles of the Wnt-beta-catenin signaling over last 2.5 decades. We have identified an important role of endothelial cells derived Wnts in regulating zone-3 hepatocyte beta-catenin activity to control target gene expression. Loss of Wnt-beta-catenin signaling led to absence of zone-3 gene expression in hepatocytes in zone-3, which now begin to express zone-1 genes. Interestingly, progressive metabolic dysfunction associated steatotic liver disease (MASLD) shows increasing loss of zone-3 and gain of zone-1 gene expression. Forced activation of Wnt signaling in advances MASLD led to improvement in steatosis, inflammation and fibrosis. Additionally, hepatocellular cancers driven by gain-of-function missense mutations in CTNNB1 (gene encoding beta-catenin) show uniform zone-3 gene expression at the expense of zone-1. This led us to identify novel metabolic vulnerabilities that allow us to treat beta-catenin mutated HCCs with selective inhibitors of mTOR and is currently being evaluated in clinical trials. Additionally, beta-catenin mutated HCCs show lack of functional T cells and B cells in the tumor microenvironment resulting in suboptimal responses to the standard of care immune checkpoint inhibitors. As a result, we evaluated direct inhibition of beta-catenin using lipid nanoparticle with siRNA against CTNNB1. This led to notable reduction in tumor burden that was associated with forced normalization of zonation within tumor nodules as well as enrichment of type I/II interferon response. This led to complete response in early tumors and a durable response in late stage disease when combined with an immune checkpoint inhibitor. Thus, forced normalization of metabolic zonation through modulation of the Wnt-beta-catenin signaling to in turn control modular gene expression could be a novel therapeutic strategy for various liver pathologies.