Funding
Pancreatic Cancer Action Network (PCAN)
Lustgarten Foundation (Lustgarten)
Stand Up To Cancer (SU2C)
Research for a cure of Pancreactic cancer
Foundation for the National Institutes of Health (FNIH)
CCSG
Princess Margaret Cancer Foundation (PMCF)
the Terry Fox Research Institute
the Canadian Cancer Society Research Institute
Pancreatic Cancer Canada Foundation (PCCF)
Ontario Institute for Cancer Research (OICR)
Syros Pharmaceuticles, Inc. Cambridge MA
Cancer Center Support
ARTICLE ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid cancers; thus, identifying more effective therapies is a major unmet need. In this study, we characterized the super-enhancer (SE) landscape of human PDAC to identify drivers of the disease that might be targetable. This analysis revealed MICAL2 as an SE-associated gene in human PDAC, which encodes the flavin monooxygenase enzyme that induces actin depolymerization and indirectly promotes serum response factor transcription by modulating the availability of serum response factor coactivators such as myocardin-related transcription factors (MRTF-A and MRTF-B). MICAL2 was overexpressed in PDAC, and high-MICAL2 expression correlated with poor patient prognosis. Transcriptional analysis revealed that MICAL2 upregulates KRAS and epithelial–mesenchymal transition signaling pathways, contributing to tumor growth and metastasis. In loss- and gain-of-function experiments in human and mouse PDAC cells, MICAL2 promoted both ERK1/2 and AKT activation. Consistent with its role in actin depolymerization and KRAS signaling, loss of MICAL2 also inhibited macropinocytosis. MICAL2, MRTF-A, and MRTF-B influenced PDAC cell proliferation and migration and promoted cell-cycle progression in vitro. Importantly, MICAL2 supported in vivo tumor growth and metastasis. Interestingly, MRTF-B, but not MRTF-A, phenocopied MICAL2-driven phenotypes in vivo. This study highlights the multiple ways in which MICAL2 affects PDAC biology and provides a foundation for future investigations into the potential of targeting MICAL2 for therapeutic intervention.Significance: Characterization of the epigenomic landscape of pancreatic cancer to identify early drivers of tumorigenesis uncovered MICAL2 as a super-enhancer–associated gene critical for tumor progression that represents a potential pharmacologic target.
