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Truncated O ‐ glycans Enhance Tumorigenicity of Pancreatic Tumors

The interaction between cancer cell surface mucins and growth factor receptors enhances the tumorigenesis of pancreatic adenocarcinoma (PDAC). The truncated O‐glycans (Tn and sialyl Tn) on mucin type glycoproteins enhances the malignant properties of cancer cells, in part by altering ligand affinities for receptors and constitutively activating oncogenic signaling pathways. Truncated O‐glycans on the cancer cell surface are often due to lack of core 3 synthase or core 1 synthase activity and/or defects in the Core 1 synthase specific chaperone ‐ Cosmc. We investigated the contribution of Cosmc to the tumorigenicity of PDAC. A human pancreatic cancer (PC) cell line was genetically targeted to knockout Cosmc with Zinc Finger Nucleases and subsequently used for evaluation of tumorigenicity. The knockout of Cosmc in PC cells resulted in activation of ErbB2 signaling pathway through increased interactions with MUC4, Tn on MUC4 and MUC16. This leads to activated PI3/AKT downstream signaling pathways and altered oncogenic gene expression. Cosmc knockout cells showed significantly increased in vitro migration, invasion and in vivo tumor growth as compared to Cosmc expressing cells. These results demonstrate that aberrant expressions of Tn or STn epitopes on glycoproteins enhance the tumorigenecity of PC cells by activating oncogenic signaling through cell surface receptors. Supported by NCI U01CA111294, U01CA128437, P50CA127297.