Despite modern advances in cancer therapy, the prognosis for pancreatic ductal adenocarcinoma (PDAC) remains dismal, highlighting the need for better understanding of the biologic underpinnings of the disease. Well established as a pathway for growth and regeneration, Wnt signaling maintains subpopulations of cancer cells in a stem-like state, contributing to the heterogeneous composition of tumors. Our previous work demonstrated that Porcupine, an essential enzyme for secretion of paracrine Wnt signals, can be used to mark Wnt-producing cells in normal and tumor tissues. We detected the presence of nuclear beta-catenin, a biomarker of active Wnt-signaling, in a subpopulation of cancer cells adjacent to Porcupine+ niche cells in murine PDAC tissue. Furthermore, genetic inactivation of Porcupine translated to a 25% increase in survival in PDAC-bearing mice. In vitro, we see a marked increase in spheroid formation and proliferation of the stem-like subpopulation over the rest of the primary tumor cells. Ongoing lineage-tracing experiments in an autochthonous murine model of PDAC will determine whether these cancer stem cells are able to produce their Wnt-secreting niche in vivo. Our current efforts are focused on the preclinical evaluation of Wnt inhibitors in the treatment of mouse and human PDAC as single agents or in combination with chemotherapy. Such findings open the door for interrogation of the Wnt pathway as a possible target for improving the clinical outcome of pancreatic cancer.

Citation Format: Katherine Wu, Olivera Grbovic-Huezo, Griffin Hartmann, Tyler Jacks, Tuomas Tammela. Wnt-producing niche cells support cancer stem-like cells in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1124.

©2018 American Association for Cancer Research.
2018
American Association for Cancer Research.