?-Catenin is a chief downstream effector of the Wnt signaling pathway. Wnt signals inhibit ?-catenin degradation complex to stabilize ?-catenin followed by its nuclear translocation. In the nucleus, ?-catenin acts chiefly as a co-activator fo T cell factor (TCF) family of transcription factors. Notable interactions of ?- catenin have now bee reported with major effectors of other key signaling pathways that divulges a complex interactome, which could have significant repercussions in human health and disease. One such interaction in the liver is that with the Hippo signaling component- Yes Associated Protein-1 (Yap). Yap, like ?-catenin, is a transcriptional co-activator, which can regulate activity of TE domain (TEAD) transcription factors. While both pathways are critical for regulating cell fate and proliferation, we made an intriguing observation of ?-catenin-Yap association in the commonest pediatric liver tumor or hepatoblastoma (HB). HB classically harbors exon-3 deletions in gene encoding ?-catenin (CTNNB1) rendering a truncated stable protein and is observed as nuclear translocation of ?-catenin in majority of HB. Interestingly, we identified human HB samples to also simultaneously show nuclear Yap as well. Further characterization in human HB cell lines identified a synergy between the two molecules in cell proliferation and survival. Co- expression of Yap and ?-catenin in liver using sleeping beauty (SB) transposon/transposase, led to robust HB within 4 weeks after injection that led to significant mortality in few weeks. This tumor model allows us a unique opportunity to address the complex interplay between ?-catenin and Yap proteins in `hepatoblastomagenesis'. We propose to characterize protein-protein interactions between the two molecules along with their transcription factors as well as elucidate downstream signaling, which is required for HB initiation and progression. Simultaneously, these studies will allow us to exploit these interactions and target genes for precision therapies against HB, a tumor which lacks molecular therapies. We will investigate the hypothesize that Yap and ?-catenin along with their respective transcription factors form a functional interactome to in turn activate a unique transcriptome, critical to development and growth of HB. We propose to comprehensively elucidate these molecular mechanisms in the 3 specific aims.
Aim 1 will determine the biochemical and genetic basis of Yap-?-catenin interactions that lead to HB development in mice and patients. The analysis will also determine role of canonical transcription factors such as TCF and TEAD as well as recently identified and timely factors such as Tbx5.
In Aim 2 we will identify downstream targets of Yap-?-catenin that lead to HB in mice and patients. This analysis will again determine the molecular basis of how Yap-?-catenin expression coerces hepatocyte reprogramming to hepatoblast and then determine the relevance of known targets like c-myc and those identified through unbiased in silico and genearray approaches. Eventually, Aim 3 will be focused at determining the effect of therapeutic targeting of ?-catenin and/or Yap treatment of HB along with the molecular basis of these observations. Thus, this proposal will be a comprehensive investigation to characterize the molecular basis of the leading pediatric liver tumor, and is bound to have significant biological and therapeutic implications.
The research proposal focuses on understanding the molecular mechanisms leading to the development of the commonest liver tumor in children. We have identified ?-catenin and Yap association and synergy in majority of hepatoblastoma tissues from patients and in cell lines. We have generated a mouse model that replicates this human disease. This proposal will assess the relevance of these interactions in tumor biology and this study will form the basis for precision molecular therapies against this pediatric tumor.
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|Russell, Jacquelyn O; Monga, Satdarshan P (2018) Wnt/?-Catenin Signaling in Liver Development, Homeostasis, and Pathobiology. Annu Rev Pathol 13:351-378|
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|Pradhan-Sundd, Tirthadipa; Vats, Ravi; Russell, Jacquelyn O et al. (2018) Dysregulated Bile Transporters and Impaired Tight Junctions During Chronic Liver Injury in Mice. Gastroenterology 155:1218-1232.e24|
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|Soto-Gutierrez, Alejandro; Gough, Albert; Vernetti, Lawrence A et al. (2017) Pre-clinical and clinical investigations of metabolic zonation in liver diseases: The potential of microphysiology systems. Exp Biol Med (Maywood) 242:1605-1616|
|Bell, Danielle; Ranganathan, Sarangarajan; Tao, Junyan et al. (2017) Novel Advances in Understanding of Molecular Pathogenesis of Hepatoblastoma: A Wnt/?-Catenin Perspective. Gene Expr 17:141-154|
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