To Identify the Predictive Exosomal Biomarkers of Sorafenib Resistance in Hcc: Targeting the Cancer-Associated Fibroblast Niche

Hepatocellular carcinoma (HCC) is the fourth most common cancer and second leading cause of cancer-related deaths which caused around 8,000 deaths in 2018 in Taiwan. Only early stage HCCs are amenable to curative therapies including surgery and local ablation. For advanced stage HCCs, sorafenib is the first and most widely used molecular targeted therapy which provides a statistically significant but clinically limited advantage due to high frequency of primary or acquired resistance. Most studies of the mechanisms of drug resistance have focused on the role of tumor cells. Growing evidence indicate that the tumor microenvironment also plays an important role in drug delivery and chemoresistance. Exosomes are nanosized membrane vesicles that are constitutively released by almost all cell types and can shuttle bioactive molecules including proteins, DNA, mRNA, as well as non-coding RNAs from one cell to another, leading to the exchange of genetic information and reprogramming of the recipient cells. Exosomes are emerging as a potential contributor to cancer progression, adding another dimension to the complexity of the tumor microenvironment. Therefore, it is conceivable that cancer exosomes could serve as a diagnostic and therapeutic target. As functional mediators of tumor-stroma interaction and of epithelial to mesenchymal transition, exosomes may also promote environment-mediated therapy resistance. Tumor-derived exosomes help cancer-associated fibroblasts (CAFs) to acquire protumorigenic properties. In the other hand, CAF-derived exosomes may also promote cancer progression and contribute to chemoresistance. The survival and growth of HCC depends on interactions with multiple factors and cell types presenting in the tumor microenvironment. The specific functions of exosomes and CAFs are believed to enhance progression and dedifferentiation of cancer stem cells and result in drug resistance of HCC therapies. To explicit the role of exosome and CAF in sorafenib resistance to HCC, three aims are proposed in this proposal:Aim 1: To examine the effect of sorafenib-resistant HCC-derived exosomes in the induction of CAF niche. Aim 2: To identify the key factors (miRNA, lncRNA, and proteins) of sorafenib-resistant HCC-derived exosome in CAF induction and sorafenib resistance.Aim 3: To validate the clinical significance of potential exosomal miRNA/lncRNA and protein factors with sorefenib resistance in HCC patients (using tissue and serum samples).

Project ID:PC10907-0864
External Project ID:MOST109-2314-B182-025