Clinical significance of dynamic monitoring of HLA DR, HLA DR bright, CD14+/CD4+, CD14+/CD16-, CD14+/CD16+ and CD14+/CD56+ monocyte expression in the prediction and evaluation of patients with acute pancreatitis

Abstract

s / Pancreatology Nevertheless, there are 4 class I PI3K isoforms with non-redundant physiological roles and debated ones in cancer. Aims: This study aims to determine in vivo role of PI3Ka isoform in KrasG12D-driven cancerogenesis. Materials & methods: Using a unique system mimicking a pharmacological intervention, we created transgenicmice expressing KrasG12D (KC) and a catalytically inactive PI3Ka. We analyzed agedand inflammationinduced-KrasG12D driven cancerogenesis. Immunohistochemistry, Immunofluorescence, Western blot, Ex-vivo culture, Pull-down assay was performed to investigate the mechanism of PI3Ka-KrasG12D cooperation in murine and human tissues. Results: Genetic inactivation of PI3Ka completelyabrogates apparition of pancreatic preneoplastic lesions (acinar-to-ductal metaplasia-ADM/PanINs) in pancreata of 6 month-old KC mice. Both genetic and pharmacological ablation of PI3Ka activity prevents caerulein-induced ADM in mice with or without mutated-Kras and allow a complete pancreatic regeneration through acinar-cell proliferation. Immune cells are recruited, embryonic transcription factors (Pdx1,p48) are activated but fibroblasts are not activated. In vivo inactivation of PI3Ka activity unable oncogenic Ras activation andmaintenance of downstreamsignalingpathways (ERK,STAT3) after acute pancreatitis. Finally, p53-mutated KC mice lacking PI3Ka activity cannot develop PDAC and p53/Kras-mutated pancreatic cancer cell lines are more sensitive to PI3Ka-specific inhibitors than Kras-mutated only cell lines. Conclusion: Our genetic and pharmacological evidence provide the rationale for PI3Ka as a target and demonstrate an unsuspected role for the non-mutated PI3Ka isoform in PDAC: PI3Ka is required for inflammation, Kras activation and Kras-driven cancerogenesis.