Accumulation of p62/sequestosome-1 in pancreatic cancer progression: association with inflammation and immune cell infiltration

Background Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer that develops from precursor lesions such as pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). The adaptor protein p62 links autophagy defects with oxidative stress and inflammatory signaling, but its role across disease stages is not well defined. We examined p62 expression together with markers of autophagy, metabolic stress responses, and inflammation in human pancreatic lesions and a Kras-driven mouse model. Methods Formalin-fixed sections from 29 patients (PanIN2/3, n=10; IPMN, n=9; PDAC, n=10) were analyzed by immunohistochemistry for p62, LC3B, NRF2, TFEB, phosphorylated NFκB p65, CD45, and CD3. Staining was quantified using digital pathology (QuPath). Parallel studies were conducted in Pdx1-Cre;LSL-Kras G12D mice aged 4–12 months, with blinded histological scoring. Results p62 expression was higher in PDAC than in PanIN2/3 and IPMN (p<0.01), while LC3B, NRF2, and TFEB showed no differences. Immune infiltration (CD45) was increased in PDAC versus PanIN2/3 (p<0.01), whereas phosphorylated NFκB p65 did not differ between groups. Correlation analysis showed stage-specific associations: p62-LC3B in PanIN2/3, p62-CD45 in IPMN, and p62-TFEB in PDAC. In mice, p62 and phosphorylated NFκB p65 followed a biphasic pattern, peaking in early lesions, decreasing in PanIN, and rising again in PDAC. Conclusion These findings show that p62 accumulation is stage-dependent and is associated with inflammatory and immune changes during pancreatic cancer progression, suggesting a potential role in the transition to invasive PDAC.