Abstract A054: MICAL2 promotes oncogenic Kras -induced pancreatic cancer initiation by regulating RAC1-mediated acinar to ductal metaplasia

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a deadly form of pancreatic cancer with the poorest 5-year survival rate among all solid cancers. Therefore, identifying effective therapeutic strategies is crucial for treating this disease. Using a genome-wide screening approach to find novel and targetable factors in human PDAC, our laboratory identified MICAL2 (microtubule-associated monooxygenase, calponin, and LIM domain containing 2) as a gene uniquely enriched in PDAC patient samples. In our recently published study, we reported that the PDAC cells are dependent upon MICAL2 for their growth and distant metastasis. These findings establish MICAL2 as a key regulator in the maintenance of PDAC. However, its role in pancreatic cancer initiation remains poorly understood. To directly test the role of MICAL2 in pancreatic cancer initiation and progression, we utilized a genetically engineered mouse model of early pancreatic tumorigenesis (LSL- K ras G12D/+ , Pdx1- C re, i.e. KC ), where we conditionally deleted the M ical2 gene ( M ical2 flox/flox ) specifically in the pancreas to understand the importance of MICAL2 (M) in the early tumor initiation. We performed comparative histological analysis and in vitro biochemical studies to identify early tumor lesions and understand the underlying molecular differences in the wild-type (KC) and the Mical2-deficient KC (KCM) mice. We found that deleting MICAL2 in a genetically engineered mouse model (GEMM) of pancreatic cancer functionally delays oncogenic Kras-induced PDAC initiation and progression. Histopathological and in vitro biochemical assays show that genetic ablation of MICAL2 impairs tumor initiation by functionally delaying the acinar-to-ductal metaplasia (ADM), which involves a significant cytoskeletal rearrangement and is linked to PDAC initiation. Additionally, extensive biochemical studies, gene expression analyses, and immunostaining reveal a significantly decreased RAC1 expression in ductal lesions upon the loss of MICAL2 during KRAS-driven pancreatic duct neoplasia. Collectively, these data indicate that MICAL2 plays a critical role during the early stages of pancreatic cancer initiation by regulating RAC1 activity during Kras-induced ADM.