Abstract 4815: Temporal control of EMT via the miR-200c/Zeb1 regulatory circuit to uncover the drivers of stemness in pancreatic cancer

Abstract Pancreatic cancer is poised to become the second leading cause of cancer-related deaths by 2030, with most fatalities resulting from metastasis. During metastatic progression, tumor cells undergo epithelial-to-mesenchymal transition (EMT), a developmental program that enhances motility, stemness, and resistance to stressors such as chemotherapy. Targeting EMT-induced cancer cells is therefore an urgent therapeutic priority. To investigate the EMT spectrum, we developed a doxycycline-inducible system that enables controlled induction of epithelial or mesenchymal states through the miR-200c/Zeb1 axis. Induction of miR-200c suppresses Zeb1 and promotes epithelial identity, whereas Zeb1 induction drives mesenchymal features. Although this regulatory circuit is well studied in other cancers, its role in pancreatic cancer remains poorly understood. Across human and mouse pancreatic cancer cell lines (PANC-1, CFPAC, FC1242, FC1199), miR-200c induction upregulates E-cadherin, while Zeb1 induction decreases E-cadherin and increases vimentin. In stemness assays, Zeb1 induction exerts minimal or even negative effects on sphere formation, whereas carcinoma cells expressing mesenchymal markers consistently display high stem-like capacity. Overexpression of miR-200c markedly suppresses the cancer stem cell phenotype, highlighting its role as a potent regulator of epithelial identity. Overall, our findings establish miR-200c as a central driver of the epithelial, less invasive state in pancreatic cancer and suggest that developing therapeutic strategies that upregulate miR-200c hold strong potential to prevent metastasis and improve overall survival for pancreatic cancer patients. Citation Format: Andrew Karam, Divya Murthy, Petra den Hollander, Joseph Zhu, Sendurai A. Mani. Temporal control of EMT via the miR-200c/Zeb1 regulatory circuit to uncover the drivers of stemness in pancreatic cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4815.