Abstract A53: ADAM12 contributes to the malignant potential of pancreatic cancer and may serve as a non-invasive biomarker for its detection

Abstract

Abstract Pancreatic malignancies are the fourth leading cause of all cancer-related deaths of both men and women in the United States. A majority of patients with pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumors (pNET) present with advanced disease due to a lack of specific symptoms. The high mortality rate associated with pancreatic cancer can be attributed to both a lack of clinical diagnostic tests for early detection as well as an inadequate understanding of the underlying molecular mechanisms of its aggressive pathogenesis. We have recently become interested in the role that ADAM12 (a disintegrin and metalloprotease 12), a member of the disintegrin metalloprotease family, may play in the development and progression of pancreatic cancer. We have found that ADAM12 protein levels are significantly upregulated in human pancreatic cancer and in mouse models of PDAC and correlate with disease progression. ADAM12 levels were also upregulated in precursor PanIN lesions in a transgenic mouse model. ADAM12 transcript and protein expression is higher in poorly differentiated/quasi-mesenchymal pancreatic cancer cell lines such as Panc1 and MiaPaca2 compared to well-differentiated/classical cell lines such as AspC1 and BxPC3. Downregulation of ADAM12 in pancreatic tumor cells resulted in reduced cell migration, invasion and proliferation whereas apoptotic rates were significantly higher. In agreement with these findings, activation of common signaling pathways including pEGFR, pSTAT3 and pErk were also downregulated in response to ADAM12 silencing in these cells. We have also determined whether ADAM12 could be detected in the urine of patients with pancreatic malignancies and whether ADAM12 levels might serve as an independent predictor of disease status. Retrospective analyses of urine samples (n=130) from PDAC and pNET patients as well as age- and sex-matched controls were conducted. Urinary ADAM12 levels were determined using a monospecific ELISA system. Multivariable logistic regression analyses indicated that, when controlling for age and sex, urinary ADAM12 could serve as significant independent predictor for distinguishing PDAC (P<0.001) and pNET (P<0.008) patients from healthy controls. Kaplan-Meier analysis of estimated patient survival stratified by urinary ADAM12 levels indicated a significantly shorter patient survival time for PDAC patients with high ADAM12 levels (P=0.015) compared to patients with lower urinary ADAM12. Taken together, our results indicate that ADAM12 is aberrantly upregulated in PDAC tumors and contributes to the malignant properties of pancreatic tumor cells. These data also support the conclusion that the measurement of ADAM12 levels may have diagnostic value in detection and/or clinical monitoring of disease status in patients with pancreatic malignancies. [Supported by: The Advanced Medical Research Foundation] Citation Format: Roopali Roy, Adelle Dagher, David Zurakowski, Matthew Kulke, Marsha A. Moses.{Authors}. ADAM12 contributes to the malignant potential of pancreatic cancer and may serve as a non-invasive biomarker for its detection. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A53.