Abstract 5007: Discovery of stromal targets in pancreatic cancer

Abstract

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with limited treatment options. Development of stroma targeting therapeutics for PDAC is gaining attention because PDAC has a unique tumor microenvironment with dense tumor stroma and the tumor stroma is a critical mediator of PDAC progression. Herein, we discovered pancreatic cancer stroma-specific cell surface markers by integrative analysis of single cell RNA sequencing and cell surface marker database. Methods: Single cell RNA sequencing data of PDAC tissue (n = 3, GSE154778) and normal pancreas tissue (n = 3, GSE131886) was obtained from Gene Expression Omnibus database. Using Seurat package, the data from each sample integrated and the cells were clustered. We selected stroma cell cluster for differential analysis to obtain the genes enriched in PDAC stroma. Then, the intersection of the PDAC stroma specific genes with the gene set of SurfaceomeDB was obtained, which allowed us to obtain the stroma cell surface markers that are highly expressed in PDAC. The marker genes were validated in 1) 36 pairs of PDAC and normal tissue samples from a RNA sequencing data (GSE15471), and 2) 143 PDAC samples in The Cancer Genome Atlas (TCGA), 328 normal pancreatic tissues in Genotype-Tissue Expression (GTEx) database (https://www.gtexportal.org). Results: The cells from PDAC and normal pancreas were clustered into ductal/tumor, stromal and immune cell clusters according to the expression of cell-type specific marker genes. We identified variably expressed genes between PDAC and normal cells within the stromal cell cluster. Among the PDAC stroma-specific genes, we could obtain 360 cell surface markers using SurfaceomeDB. The top ten PDAC stroma-specific cell surface marker genes were MXRA8, ANTXR1, THY1, SCD1, LY6E, BST2, GPNMB, CDH11, GJB2, and CD55. To validate the results, we compared the expression levels of the top 10 genes between pancreatic cancer tissue and adjacent normal pancreatic tissue. We found that the expression levels of the genes were significantly higher in the cancer tissue compared to the normal pancreatic tissue. We also confirmed that the expression levels of 10 genes were significantly higher in all stages of PDAC compared to normal tissues in a combined RNA sequencing dataset from healthy human pancreatic tissue from GTEx and pancreatic cancer patients from TCGA. Conclusion: We identified pancreatic cancer stroma-specific cell surface markers using single-cell RNA sequencing data and SurfaceomeDB. The markers can be utilized in development of various pancreatic cancer stroma targeted therapeutics including antibodies, antibody-drug conjugates, peptides, cell therapeutic and nanoparticles. Citation Format: Shengjun Li, Jeong-Bin Park, Hyung-Jun Im. Discovery of stromal targets in pancreatic cancer [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 5007.