MICAL2 Promotes Pancreatic Cancer Growth and Metastasis

作者：Bharti Garg, Sohini Khan, Asimina S. Courelli, Ponmathi Panneerpandian, Deepa Sheik Pran Babu, Evangeline Mose, Kevin Christian Montecillo Gulay, Shweta Sharma, Divya Sood, Alexander T. Wenzel, Alexei Martsinkovskiy, Nirakar Rajbhandari, Jay Patel, Dawn Jaquish, Edgar Esparza, Katelin Jaque, Neetu Aggarwal, Guillem Lambies, Anthony D’Ippolito, Kathryn Austgen, Brian Johnston, David Orlando, Gun Ho Jang, Steven Gallinger, Elliot Goodfellow, Pnina Brodt, Cosimo Commisso, Pablo Tamayo, Jill P. Mesirov, Hervé Tiriac, Andrew M. Lowy · 发表于：Cancer Research · 年份：2025 · DOI：10.1158/0008-5472.can-24-0744 · 被引用次数：8 · 研究领域：Adenosine and Purinergic Signaling、Pancreatic and Hepatic Oncology Research、Angiogenesis and VEGF in Cancer

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 a...