Abstract C20: Smpd3 augments chemotherapy and thwarts PDA progression

Abstract

Abstract Deregulated sphingolipid metabolism alters pancreatic cancer progression; for that reason, bioactive lipid signaling molecules such as ceramide show promise as both biomarkers for disease progression and novel therapeutic targets. Intracellular ceramide levels are critical for regulating cellular senescence, apoptosis, and cell cycle arrest in response to stress stimuli such as chemotherapeutics. Our data show Sphingomyelin Phosphodiesterase 3 (Smpd3), a regulator of ceramide synthesis and exosome biogenesis, has a protumorigenic function in pancreatic ductal adenocarcinoma (PDA). Immunodeficient mice orthotopically implanted with Smpd3-deficient PDA cell lines demonstrate significantly reduced tumor burden and longer survival when compared with controls. This observation was mirrored by our KPC; Smpd3f/f mouse model, in which loss of Smpd3 expression significantly correlated with longer survival and decreased metastasis when compared to KPC; Smpd3wt/wt controls. Analysis of SMPD3 in PDA patients revealed that low SMPD3 RNA and protein expression is significantly associated with worse survival. Because chemotherapeutics have been shown to affect expression and function of SMPD3, we stratified patient cohorts into individuals who received adjuvant chemotherapy, more than 95% of which was gemcitabine, and those who did not receive adjuvant chemotherapy. We found that high SMPD3 expression in surgically resected PDA significantly correlated with longer patient survival only in patients receiving adjuvant chemotherapy, and not in the no-adjuvant-chemotherapy group. These data suggest an interaction between adjuvant chemotherapy with gemcitabine and SMPD3 expression. Furthermore, we found that gemcitabine stimulates both the enzymatic activity and expression of SMPD3 in vitro in a panel of human PDA cell lines. Our results suggest a crucial role for SMPD3 in facilitating a protumorigenic environment during PDA progression and implicate SMPD3 as a potential novel biomarker for guiding individualized chemotherapeutic regimens for PDA patients. Citation Format: Audrey M. Hendley, Atsushi Urano, Natanya R. Kerper, Phat Duong, Peter Bailey, David K. Chang, Andrew V. Biankin, David W. Dawson, Grace Kim, Robert L. Raffai, Matthias Hebrok. Smpd3 augments chemotherapy and thwarts PDA progression [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C20.