ZIA BC 010313 (ZIA) | |||
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Title | Molecular signatures for liver cancer diagnosis and treatment stratification | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Wang, Xin Wei | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $728,028 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2017 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Digestive Diseases (100.0%) Genetic Testing (30.0%) Metastasis (50.0%) |
Liver Cancer (90.0%) | ||
Research Type | |||
Cancer Initiation: Oncogenes & Tumor Suppressor Genes Cancer Progression & Metastasis |
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Abstract | |||
We are using global genomic approaches to profile clinical specimens that are associated with different stages of liver diseases. We have identified a unique diagnostic signature for patients with early onset of liver cancer and have also developed a unique molecular signature based on the mRNA gene expression of metastatic primary hepatocellular carcinoma (HCC) specimens to predict prognosis and metastasis of HCC patients. We found that this molecular signature could identify those patients who were most at risk for recurrence even in patients with early stage disease. More recently, we integrated genomic and transcriptomic profiles to search for metastasis driver genes. We found that primary tumor lesions and their match distant metastasis were similar, however significant differences could be identified between primary tumors with or without accompanying metastasis. Moreover, metastasis genes were principally tumor type and organ-site-specific, further solidifying that metastatic propensity is inherent to the primary tumor. We have also developed a unique molecular prognostic signature based on mRNA gene expression of the liver microenvironment of HCC patients. We found that a predominant humoral cytokine profile occurs in the metastatic liver microenvironment and that a shift toward anti-inflammatory/immune-suppressive responses may promote HCC metastases. Interestingly, the tumor signature is principally different from that of liver microenvironment. We have recently explored whether activated hepatic stellate cells (A-HSCs) contribute directly to HCC recurrence. We identified and validated an A-HSC-specific gene expression signature among nontumor tissues of HCC patients that was associated with HCC recurrence and survival. Further studies showed that A-HSCs preferentially alter monocyte populations to induce protumorigenic and progressive features by shifting their gene expression from an inflammatory to an immune suppressive signature. These findings indicate that disruption of the interactions and signaling events between inflammatory cells and components of the microenvironment may be useful therapeutic strategies for preventing HCC relapse. We have also found that small non-coding RNAs, termed microRNAs are associated with metastasis and could significantly predict patient survival and relapse even in early stage disease, while certain microRNAs (e.g. microRNA-26) are gender-related. Patients with low microRNA-26 expression had poor survival and were better responders to interferon therapy than those with normal expression. We developed a qRT-PCR-based matrix template and scoring algorithm (MIR26-DX) to assign patients into either low or high microRNA-26 groups. Patients with low microRNA-26 levels selected by the template were those that responded favorably to interferon-alpha therapy. We have now initiated a multi-center randomized control clinical trial in China based on these findings (NCT01681446). We have also used integrative approaches to identify HCC driver genes. We have combined high-resolution, array-based comparative genomic hybridization and transcriptome analysis of HCC samples to identify and validate a 10-gene signature associated with chromosome 8p loss and poor outcome. Functional studies demonstrated that three gene products have tumor suppressive properties and two of these genes, SORBS3 and SH2D4A, are linked and inhibit STAT3-mediated IL-6 signaling in HCC cells. We have also integrated metabolite and mRNA profiles to define key signaling events of HCC cancer stem cells. Our analysis revealed that stearoyl CoA desaturase (SCD), a key enzyme involved in fatty acid biosynthesis, and its related metabolites were highly elevated in stem cell-like HCC and are associated with HCC survival and aggressiveness. In a comparison of global metabolic profiles between liver, breast and pancreatic cancer tissues, we found that metabolites are principally unique to each tissue and cancer type. Thus, metabolic |