Abstract A034: Spatial multi-omics defines cancer-like precursor lesions in human pancreas

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive type of pancreatic cancer classically driven by oncogenic KRAS mutations. It is thought to arise from precursor lesions including intraductal papillary mucinous neoplasia (IPMN) and pancreatic intraepithelial neoplasia (PanIN). We have recently reported that PanINs are common and heterogenous in healthy individuals; they harbor some basal-like and classical-like histologic pattern previously reported in PDAC. However, there are limited studies on the molecule profile and transformative risk of panIN phenotypes. In partnership with Gift of Life Michigan, we collected 127 pancreases from donors, aged 21 to 76 years. Additionally, we have collected PDAC surgical samples. We performed Single-cell RNA-sequencing (ScRNA-seq) on 32 specimens and spatial transcriptomics (GeoMx) on 12 specimens including donor, adjacent normal, and tumors. Tissues were also formalin-fixed, paraffin-embedded, and sectioned for multiplex immunofluorescence staining (MIFs). Differential analysis of spatial and Sc-RNA-seq datasets showed high expression of KRT17, CXCL5, and LAMC2 in basal PDAC and basal-like panINs relative to classical tumor and classical-like panINs. Additionally, there were marked differences in WNT pathway related genes such at DKK1. While we noted a remarkable high number of LAMC2+ cells in KRT17+ tumors and adjacent normal tissues, few KRT17+ panINs were LAMC2+. Additionally, MIF revealed direct and inverse relationships between the WNT pathway inhibitor DKK1 and KRT17 levels in tumor and lesions, respectively, suggesting that basal like cells are present in PanINs may have distinct differences in WNT signaling compared to tumors. Overall, our work revealed high DKK1 activity in most classical-like panINs but low DKK1 basal-like panINs. This suggests that DKK1 may have a role in epithelial cellular identity in both PanINs and tumors. More works are needed to further characterize the impact of WNT signaling on PanIN progression.