Abstract 4892: Pentraxin 3: A stromal derived diagnostic biomarker for pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a dismal prognosis and 5 year survival rate of less than 5%. Desmoplastic reaction, characterized by the proliferation of myofibroblast-like cells (also known as activated pancreatic stellate cells (PSCs)) and the significant deposition of extracellular matrix components, such as hyaluronan, is a prominent pathological characteristic of PDAC and significantly contributes to its chemoresistance. All trans retinoic acid (ATRA) is a pleiotropic agent modulating multiple signaling pathways that renders activated PSCs quiescent. Previous work from our laboratory demonstrated various phenotypic changes in ATRA-treated PSCs and comparative gene expression microarray analysis revealed that the pentraxin-related protein 3 (PTX3) expression is down-regulated in quiescent PSCs compared to activated PSCs. Since PTX3 plays a key role in the formation of the hyaluronan-rich matrix via its interaction with tumor necrosis factor stimulated gene 6 (TSG-6) and hyaluronic acid (HA) chains, we sought to investigate the role of PTX3 in PDAC and to assess it as a potential diagnostic biomarker for patients with pancreatic cancer. Serum PTX3 concentrations were evaluated in 140 patients with PDAC and 138 controls (healthy individuals, patients with other pancreatic diseases or inflammatory conditions) by ELISA. To establish the source of PTX3 secretion we analyzed in vitro cell cultures of PSCs and cancer cell lines. PTX3 specificity was confirmed upon PTX3 siRNA analysis by western blot and qPCR. Three-dimensional organotypic cultures, KPC mice and human tissue were assessed by immunohistochemistry. Expression of TSG-6 and HA were also evaluated using immunofluorescence studies. Our results showed that patients with PDAC had significantly higher serum PTX3 concentrations than patients with other pancreatic diseases and healthy individuals. ROC curve analysis confirmed the reliability of PTX3 serum levels in diagnosing pancreatic cancer with a sensitivity and a specificity of 86%. Western blotting, qPCR and immunofluorescence validated that activated PSCs produce and secrete PTX3 and its expression was down-regulated on rendering these cells quiescent upon ATRA treatment. Organotypic models elucidated that hyaluronan is expressed and secreted by the PSCs and the analysis of human and mouse tissues demonstrated predominant PTX3 expression in the stromal compartment of PDAC. Our study identified that serum PTX3 is a sensitive and specific diagnostic biomarker for PDAC with the ability to separate malignant from other benign conditions of the pancreas. Activated PSCs are the main source of PTX3 secretion and contribute to the formation and stabilization of the PDAC extracellular matrix architecture. Citation Format: Michelle R. Goulart, Jennifer Watt, Imran Siddique, Rita Lawor, Thomas Dowe, Satyajit Bhattacharya, Tatjana Crnogorac-Jurcevic, Paola Allavena, Aldo Scarpa, Hemant M. Kocher. Pentraxin 3: A stromal derived diagnostic biomarker for pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4892.