MICAL2通过调控腺泡向导管化生促进致癌性Kras诱导的胰腺癌起始

Background: 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, we identified MICAL2 (microtubule-associated monooxygenase, calponin, and LIM domain containing 2) as a gene uniquely enriched in PDAC patients. Our research has shown that MICAL2 is highly expressed in human PDAC and is linked to a worse prognosis for patients. Additionally, tumor growth and distant metastasis are reduced in PDAC tumors silenced for MICAL2. Although these findings establish MICAL2 as a key regulator in PDAC, its role in pancreatic cancer initiation and progression remains poorly understood. Methods: 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 Mical2 gene (Mical2 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 differences in the wild-type (KC) and the Mical2-deficient KC (KCM) mice. Results: Our preliminary studies indicate that deleting MICAL2 in a genetically engineered mouse model (GEMM) of pancreatic cancer functionally delays PDAC initiation and progression. Biochemical and histopathological analysis show that removing MICAL2 impairs oncogenic KRAS-induced 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 significant decrease in RAC1 and ARP2 expression, along with reduced EGFR and PI3K/AKT activity when MICAL2 is inhibited during KRAS-driven pancreatic duct neoplasia. Conclusions: Our observations indicate that MICAL2 plays a crucial role downstream of oncogenic Kras during the early stages of pancreatic cancer initiation by regulating RAC1 and ARP2, as well as EGFR and PI3K/AKT activity, which are necessary for Kras-induced ADM. This suggests that inhibiting MICAL2 could be a viable target for prevention and therapeutic strategies in PDAC.