Abstract 2522: Pathway and immune profile analysis of cyst-derived versus PanIN-derived pancreatic ductal adenocarcinomas
Authors: Park Margaret A. , Krishna Somashekar G. , Genilo-Delgado Maria C. , Gumpper-Fedus Kristyn , Conwell Darwin L. , Hart Phil A. , Dillhoff Mary E. , Gomez Maria F. , Basinski Toni L. , Dam Aamir N. , Klapman Jason B. , Fleming Jason B. , Malafa Mokenge , Mohammadi Amir , Centeno Barbara A. , Jiang Kun , Jeong Daniel , Chen Dung-Tsa , Xie Mengyu , Tan Aik Choon , Fridley Brooke L. , Teer Jamie K. , Cruz-Monserrate Zobeida , Permuth Jennifer B. 
Published: June 2022

Abstract
Introduction: Pancreatic cystic lesions (PCL) are common and a subset of mucinous cysts will transform into pancreatic ductal adenocarcinoma (PDAC). However, predicting which of these mucinous PCL may progress to PDAC and warrant surgery remains a clinical challenge. Moreover, identifying those clinically emergent mucinous PCL for which a surveillance approach is best is a dire clinical need. Therefore, we aimed to identify molecular signatures that distinguished between PDAC with and without clinical evidence of a PCL to identify novel biomarkers.
Methods: We leveraged data from the Oncology Research Information Exchange Network (ORIEN) multi-institute sequencing project and analyzed 66 PDAC cases recruited to ORIEN from The Ohio State University Wexner Medical Center and Moffitt Cancer Center for which tumor whole transcriptome sequencing datasets were generated. We separated the cases based on whether a tumor had originated from a cystic lesion (n=16) or presumably through the pancreatic intraepithelial neoplasia (PanIN) pathway (n=50). We then performed differential expression and pathway analysis using both Gene-Set Enrichment Analysis (GSEA) and Pathway Analysis with Down-weighted Genes (PADOG) algorithms. Based on the emerging importance of the immune landscape in PDAC development, we also analyzed immune profiles using a novel tool, Tumor-immune Microenvironment Deconvolution Web-portal for Bulk Transcriptomics (TIMEx).
Results: When grouped by tumor origin, cyst-derived PDAC gene expression sets are enriched in immune signaling pathways, specifically NOTCH signaling (p=0.04), and demonstrate significant downregulation in amino acid metabolism, mitochondrial import and Gsα signaling pathways. Furthermore, GSEA based on TIMEx signatures indicated that multiple immune cell-specific profiles had significant enrichment scores in either the cyst-derived (for example, plasma cell: normalized enrichment score=-1.53; p=0.007) or non-cyst-derived (for example, neutrophil: normalized enrichment score=2.24; p=0.0001) PDAC cohorts.
Conclusions: Our data suggest that cyst-derived and non-cyst-derived PDACs differ by immune profile, enhanced NOTCH pathway usage and in the metabolic processing of multiple amino acids. These initial findings support future studies to assess the accuracy of risk stratifying PCLs based on their amino acid, metabolic, or immune profiles, and exploration into mechanisms to explain these findings.
Citation Format: Margaret A. Park, Somashekar G. Krishna, Maria C. Genilo-Delgado, Kristyn Gumpper-Fedus, Darwin L. Conwell, Phil A. Hart, Mary E. Dillhoff, Maria F. Gomez, Toni L. Basinski, Aamir N. Dam, Jason B. Klapman, Jason B. Fleming, Mokenge Malafa, Amir Mohammadi, Barbara A. Centeno, Kun Jiang, Daniel Jeong, Dung-Tsa Chen, Mengyu Xie, Aik Choon Tan, Brooke L. Fridley, Jamie K. Teer, Zobeida Cruz-Monserrate, Jennifer B. Permuth. Pathway and immune profile analysis of cyst-derived versus PanIN-derived pancreatic ductal adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2522.