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Simple Summary: As pancreatic cancer is a disease with a high fatality rate, a better understanding of how it develops and the identification of new potential targets for its treatment are greatly needed. In this current study, we showed that the expression of amyloid precursor-like protein 2 (APLP2) in pancreatic cancer epithelial cells is higher than in precursor lesion epithelial cells, thus indicating that APLP2 increases during human pancreatic cancer development. We also generated a new mouse model that demonstrated the deletion of APLP2 expression specifically within the pancreas prolongs survival and decreases metastasis for mice with pancreatic cancer. Taken together, these findings open a new avenue toward comprehending and treating pancreatic cancer. In the United States, pancreatic cancer is a major cause of cancer-related deaths. Although substantial efforts have been made to understand pancreatic cancer biology and improve therapeutic efficacy, patients still face a bleak chance of survival. A greater understanding of pancreatic cancer development and the identification of novel treatment targets are desperately needed. Our analysis of gene expression data from patient samples showed an increase in amyloid precursor-like protein 2 (APLP2) expression within primary tumor epithelium relative to pancreatic intraepithelial neoplasia (PanIN) epithelial cells. Augmented expression of APLP2 in primary tumors compared to adjacent stroma was also observed. Genetically engineered mouse models of spontaneous pancreatic ductal adenocarcinoma were used to investigate APLP2′s role in cancer development. We found that APLP2 expression intensifies significantly during pancreatic cancer initiation and progression in the LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mouse model, as shown by immunohistochemistry analysis. In studies utilizing pancreas-specific heterozygous and homozygous knockout of APLP2 in the KPC mouse model background, we observed significantly prolonged survival and reduced metastatic progression of pancreatic cancer. These results demonstrate the importance of APLP2 in pancreatic cancer initiation and metastasis and indicate that APLP2 should be considered a potential therapeutic target for this disease. [ABSTRACT FROM AUTHOR]