Abstract
Background: Pancreatic cancer is the third leading cause of cancer-related deaths due to its poor prognosis and highly malignant nature. The altered expression of glycans and glycoproteins is associated with malignancy. MUC16 (also known as CA125) is a member of mucin family of glycoproteins known to line epithelial cells for protection and lubrication and is overexpressed in several cancer types, including pancreatic cancer, often linked with enhanced disease progression, metastasis, and reduced patient survival. Significance: Circulating levels of MUC16/CA125 has been used as a biomarker to monitor adenocarcinoma for decades. However, the functional role of CA125/MUC16 is yet to be elucidated due to a lack of studies on its large, heavily glycosylated structure and unknown functional domains. We present evidence that in addition to serving as a biomarker, circulating MUC16 has pro-tumorigenic activities. Hypothesis: Based on recent findings, we hypothesize that isoforms of MUC16 have high avidity for ErbB receptor and integrin complexes, with concomitant activation of downstream signaling cascades that include Akt and FAK, respectively. These result in the increased tumorigenic potential of pancreatic cancer cells in an autocrine manner. Experimental Design: There are four members of ErbB receptors; where receptor dimerization is a function of ligand binding and results in distinct downstream oncogenic signaling cascades. We evaluated the binding of MUC16 to different ErbB receptors, and its capacity to activate downstream signaling pathways using pancreatic cell line models that have different combinations of knock out/down of each ErbB receptor. We evaluated the global changes in the phosphorylation of oncogenic signaling molecules due to MUC16 binding using Reverse Phase Protein Array (RPPA). Results: We found that MUC16 activates Erbb4 (Y1162) along with other members of ErbB receptor family, where glycosylation of MUC16 is crucial for its biological activity. MUC16 enhanced oncogenic signaling through the phosphorylation of various downstream molecules and activated PI3K, RTK, MAPK, and DNA repair pathways. Our future directions include elucidating the molecular mechanism by which MUC16 activates the oncogenic signaling cascades via binding to ErbB receptors using our pancreatic cell line-based models. Conclusions: Understanding the biological activity of MUC16 and its cleaved product will further help in investigating the role of MUC16 in tumor microenvironment and at distant organ sites to influence the metastatic niche.
Citation Format: Amina Baniya, Michael A. (Tony) Hollingsworth. Study of MUC16/ERBB axis in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A069.
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