V-ATPase immuno-labeling demonstrates a progressive increase in intensity and loss of polarity from early PanIN lesions to pancreatic ductal adenocarcinoma (PDAC). Immunohistochemical staining of v-ATPase was graded by two independent pathologists based on intensity (upper panel) and distribution within the cells (lower panel) in randomly selected fields. The intensity score for normal ducts (1.24±0.43), low grade PanINs (1.72±0.45), high grade PanINs (2.56±0.50) and PDAC (all 3+) were significantly different among the groups, P<0.001. While the majority of normal pancreatic ducts showed a faint mixed basal/apical v-ATPase pattern, low grade PanINs mostly (86%) had a basal v-ATPase distribution within cells. The majority (94%) of high grade PanINs and all the PDAC had a diffuse distribution of v-ATPase compared to low grade PanIN lesions, P<0.001.