%0 Journal Article
%T Reduced Sod2 Expression Promotes the Development of Atypical Flat Lesions and Dysplasia during Pancreatic Ductal Adenocarcinoma Progression
%A Sara Al-Fahd
%A Noura Al-Khalifa
%A Omar Al-Turki
%J Archive of International Journal of Cancer and Allied Science
%@ 3108-4834
%D 2024
%V 4
%N 2
%R 10.51847/aIi39t3aeo
%P 212-229
%X Mitochondrial reactive oxygen species (mROS) promote acinar-to-ductal metaplasia (ADM), an early step in the development of pancreatic ductal adenocarcinoma (PDAC). Manganese superoxide dismutase (SOD2, also known as MnSOD), the primary mitochondrial ROS detoxifier, shows reduced mitochondrial activity linked to higher PDAC risk, highlighting its clinical importance. Nevertheless, the precise function of SOD2 in PDAC development and progression remains unclear. We investigated SOD2’s involvement in PDAC onset and progression by crossing Sod2fl/fl mice with the p48Cre; LSL-KrasG12D (KC) model. Additional experiments used primary mouse acinar cells and macrophages to study ADM, ROS production, and early events that suppress Sod2. Clinical relevance was evaluated using human expression datasets and tissue samples. SOD2 levels decline in low-grade lesions, yet its deletion by itself does not trigger lesion development. When combined with oncogenic Kras, Sod2 knockout enhances dysplasia and cancer stem cell emergence within the standard PDAC progression route. It also elevates the occurrence of oxidative stress-resistant atypical flat lesions (AFLs), an understudied direct precursor to PDAC. Oncogenic Kras impairs mitohormesis—the adaptive response in which mitochondrial stress triggers protective mechanisms that improve cell survival. Signals from inflammatory macrophages lower Sod2 expression, elevating ROS and driving ADM and canonical PanIN progression. In contrast, atypical flat lesions (AFLs) upregulate compensatory antioxidants such as GPX4 and NRF1, which reduce senescence and lipid peroxidation. Additional inflammatory pressure increases dysplasia, hastening tumor development, while AFLs contribute to more poorly differentiated tumor regions. This holds clinical importance because poorly differentiated human PDAC is associated with worse survival and exhibits reduced SOD2 expression.
%U https://smerpub.com/article/reduced-sod2-expression-promotes-the-development-of-atypical-flat-lesions-and-dysplasia-during-pancr-tvvxvfiradd2fpv