Abstract A055: Context-dependent role of acid sphingomyelinase in pancreatic ductal adenocarcinoma

Abstract

Abstract Sphingolipids, a class of lipids that includes the bioactive molecules ceramide and sphingosine-1-phosphate (S1P), play a contrasting role in the regulation of cancer cell death and survival. Acid sphingomyelinase (SMPD1) is the key enzyme that breaks down sphingomyelin into ceramide, accounting for more than 50% of the cellular ceramide supply and influencing the development of cancer. Here, we studied the role of SMPD1 in different cellular compartments during pancreatic ductal adenocarcinoma (PDAC) carcinogenesis. We performed a targeted quantitative plasma metabolite analysis of 637 patients (PDAC, 356; nonpancreatic disease, 281). We completed the IHC multiplex staining in the TMA of 124 patients with PDAC. Using CRISPR-Cas9 gene editing, SMPD1 was deleted in PDAC cell lines. The influence of SMPD1-KO on proliferation, colony formation, and migration was studied. Tumor progression and carcinogenesis was monitored in an orthotopic PDAC model and metastasis models using SMPD1 null cells, as well as in KC and KPC mice. Plasma metabolite analysis of 637 patients (PDAC, 356; nonpancreatic disease, 281) revealed the most pronounced changes in the group of complex lipids with the highest prevalence of sphingomyelins and ceramides. Overall survival was significantly correlated with high SMPD1 expression in tumor tissue in two independent cohorts. Interestingly, IHC multiplex analysis of SMPD1 'high expression' in cancer cells was associated with poorer survival, while SMPD1 'high expression' in immune cells was associated with longer overall survival. Expression level of Smpd1 differed from preneoplastic to neoplastic lesions in PDAC mouse tissue. Smpd1-KO in PDAC cell lines resulted in decreased proliferation, colony formation, and migration. In an orthotopic mouse model, Smpd1-KO clones resulted in significantly lower tumor weight and size compared to WT clones. Furthermore, the injection of WT clones into global Smpd1het-KO mice resulted in a significant increase in tumor weight compared to the injection of WT clones into WT mice. In two different metastasis models, injecting Smpd1-KO led to a significantly reduced formation of metastases in the lung and liver compared to WT clones. Interestingly, injecting WT clones into global Smpd1het-KO mice resulted in a significant decrease in metastasis formation in the lung compared to the injection of WT clones into WT mice. In general, we show a significant increase in survival in an orthotopic PDAC model using PDAC Smpd1-KO cells. In conclusion, SMPD1 has a context-dependent role in cancer cells and immune cells in PDAC. Inhibition of SMPD1 specifically in cancer cells is a viable therapeutic option, which should be explored in future studies. Citation Format: Ahmed Alnatsha, Qi Li, Klea Ricku, Prince Allawadhi, Jianying Xu, Didem Saka, Theresa Weltermann, Quan Zhaou, Nicole Schreiner, Kirsten Lauber, Ivonne Regel, Ujjwal Mukund Mahajan, Julia Mayerle. Context-dependent role of acid sphingomyelinase in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A055.