The central focus of this proposal is to understand the role of aspartate beta-hydroxylase (ASPH) in tumorigenesis of cholangiocarcinoma (CCA) and investigate the therapeutic potential of targeting ASPH in preclinical CCA models. The long-term goal of this proposal is to investigate potential targeting approaches for CCA patients. The overall survival of CCA patients with distant metastasis is about 7% and most patients with CCA tumors have no effective therapies. Thus, there is a need to develop an effective therapy for those patients with this deadly disease.
We have found that ASPH, which is a 2-oxoglutarate dependent enzyme, is highly expressed in CCA tumors but barely detectable in normal bile ducts. Our pilot studies demonstrated its oncogenic characteristics in CCA progression. Furthermore, we revealed a novel mechanistic link YAP1/ASPH/Notch1/Pin1/RB1 signaling cascade in cholangiocarcinogenesis. More importantly, we show that the YAP1 inhibitor-Verteporfin (VER) substantially suppressed ASPH expression and CCA malignancy.
Based on these findings, we hypothesize that the ASPH/RB1 signaling cascade mediated by YAP1 contributes to the early tumorigenesis and late malignant tumor progression of CCA. Three specific aims are proposed to determine the role of ASPH in CCA tumorigenesis. In aim 1, we will determine the effects of ASPH manipulation on CCA tumorigenesis by using different CCA models in vitro and in vivo. Aim 2 will investigate the mechanisms by which ASPH modulates CCA progression via multiple molecular approaches including RNA sequencing. In aim 3, we will repurpose the therapeutic potential of VER in CCA malignancy by using multiple CCA models, including patient-derived xenograft models.
Accomplishment of this study will 1) determine the timing of targeting ASPH either as a chemopreventive or chemotherapeutic approach, 2) provide new and critical insights into ASPH’s mechanism of action in CCA development which is crucial for targeting ASPH to treat CCA, and 3) verify the potential of VER, which targets the YAP1/ASPH/RB1 axis, as a treatment in CCA preclinical models.
Time, eligibility, and other details
| Expected workload | 1. Protein analysis by using western blotting 2. Mouse genotyping by using PCR and DNA electrophoresis |
| Skills required | Responsibility |
| Who is eligible | 2nd or 3rd year undergraduate who is interested in biomedical research |
| Core partners | |
| Sponsoring party | Faculty sponsored |
| Volunteer, Paid, or Credit-eligible? | Paid or credit-eligible |
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