Hepatocellular carcinoma (HCC) causes the 3rd most cancer related deaths worldwide, only a 5- year survival rate of 12%, and over 70% of HCC cases are diagnosed late-stage. In late stage, HCC has developed a complex molecular and cellular network in order to survive. The complexity of this system makes treatment of HCC difficult. Understanding the molecular and cellular processes in HCC opens the door to possible treatment methods. To aid in the understanding of HCC function and therapeutic response, the parent proposal embeds cell signaling networks with states determined by genomic data in multi-scale mathematical models. Preliminary work by Dr. Fertig and Dr. Popel has used such a cellular signaling network of the HGF/Met pathway to model HCC [1]. Independently, Dr. Fertig has demonstrated that alternative splicing can dysregulate cellular signaling pathways in absence of mutations or copy number alterations [2]. This supplement to the associated parent grant will provide a framework for evaluating alternative splicing events and their relation to functional changes in HCC to enhance the signaling networks in the mathematical models.
By exploring alternative splicing events and their relation to functional changes in HCC, this supplement adds an emerging method to the characterization of HCC biologically. The establishment of a junction-oriented, indiscriminate method for evaluating alternative splicing events and their associated functionality will also establish a framework for accurately evaluating and representing the complexity of alternative splicing between bulk and single-cell analysis. The analysis of alternative splicing events in HCC from this supplement will be used to enhance the molecular signaling networks and subsequently input to the mathematical models in the parent grant to predict therapeutic outcomes.
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