Abstract 240: Study of MUC16/ERBB axis in pancreatic cancer
Authors: Amina Baniya, Michael (Tony) A. Hollingsworth
Journal: Cancer Research (2025)

Pancreatic cancer is the third leading cause of cancer-related deaths due to its poor prognosis and highly malignant nature. About 65% of pancreatic cancer cases express the biomarker CA125, encoded by the MUC16 gene. MUC16 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. MUC16 has a large extracellular domain containing unstructured N-terminal domain and variable number tandem repeat domain with SEA domain, and short carboxy terminal domain. TR1.2 is a recombinant peptide containing SEA domain 5. Circulating levels of MUC16/CA125 has been used as a biomarker to monitor adenocarcinoma for decades. In serum, CA125 sizes range from 200-2000 kDa and contain SEA domains. However, functional roles of CA125/MUC16 have not been elucidated. We present evidence that in addition to serving as a biomarker, circulating MUC16 has pro-tumorigenic activities by engaging ERBB receptors. We hypothesize that isoforms of MUC16 engage ErbB3 receptors, enhancing ERBB2-EGFR heterodimerization upon ligand binding to redirect oncogenic signaling in pancreatic cancer, with concomitant activation of downstream signaling cascades that include Akt. We evaluated the influence of MUC16 (TR1.2) on ErbB receptor activation, and its capacity to activate downstream signaling pathways using pancreatic cell line models. We used alphafold3 to model the binding of TR1.2 to different ERBB receptors. We found that in serum starved conditions, TR1.2 induced a transient, yet significant downregulation of ERBB3 phosphorylation, accompanied by a slight reduction in ERBB2 phosphorylation, with no observable changes in EGFR phosphorylation in time- and dose- dependent manner. By 15 hours, phosphorylation levels returned to baseline, indicating the transient changes in serum-starved conditions. In contrast, in the presence of serum-containing media, we found significant increases in ERBB2 and EGFR phosphorylation after 15 hours treatment. Alphafold3 predicted that TR1.2 binds to domain 1 of ERBB3 causing conformational changes leading to blocking of dimerization. Together, our results suggest that TR1.2 directly binds to ERBB3 to enforce a monomer conformation. This in turn allows ERBB2 to preferentially heterodimerize with EGFR in the presence of EGF-type ligands in complete media, thereby enhancing downstream oncogenic signaling through AKT. Our future directions include validation of binding of TR1.2 to ERBB3 receptor and investing the activation of alternative pathways (such as MAPK) in pancreatic cancer cell line-based models. Understanding the biological activity of MUC16 and its cleaved product (CA125) provide insight into the role of MUC16 in the autocrine setting, the tumor microenvironment and at distant organ sites to influence the metastatic niche. Citation Format: Amina Baniya, Michael (Tony) A. Hollingsworth. Study of MUC16/ERBB axis in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 240.