Downregulation of Sod2 increases atypical flat lesions and dysplasia to advance pancreatic ductal adenocarcinoma

Production of mitochondrial reactive oxygen species (mROS) induces acinar-to-ductal metaplasia (ADM), an initiating step towards pancreatic ductal adenocarcinoma (PDAC). Manganese superoxide dismutase (SOD2, MnSOD) is the major mitochondrial ROS scavenger and less active SOD2 at the mitochondria increases risk of developing PDAC, indicating clinical relevance of SOD2. However, the role of SOD2 in PDAC tumorigenesis remains elusive. To determine SOD2’s role in PDAC initiation and progression, we crossed Sod2fl/fl mice into the p48Cre;LSL-KrasG12D (KC) mouse model. We also utilized mouse primary acinar cells and macrophages for in vitro ADM and ROS assays, and to evaluate initiating events downregulating Sod2. Human expression data and tissue assessed clinical relevance. SOD2 is downregulated in low-grade lesions, but knockout alone is insufficient for lesion formation. In conjunction with oncogenic Kras, knockout of Sod2 facilitates dysplasia and cancer stem cell formation in the canonical PDAC progression pathway but also increases presence of oxidative stress-resistant atypical flat lesions (AFLs), which are an understudied direct precursor to PDAC. Oncogenic Kras suppresses mitohormesis, a process whereby mitochondrial stress upregulates stress-reducing protective responses to enhance cell viability. Inflammatory macrophage signaling decreases Sod2 expression, increasing ROS and promoting ADM and canonical PanIN progression or alternatively, compensatory antioxidants GPX4 and NRF1 are upregulated in atypical flat lesions (AFLs), decreasing senescence and lipid peroxidation. With additional inflammation, increased dysplasia results in accelerated tumor formation and the presence of AFL leads to more poorly-differentiated tumor areas. This is of clinical significance, as poorly-differentiated human PDAC has a lower survival rate, and these tumors show less SOD2 expression.