Evolution of the Spatial transcriptomic landscape during the progression of high-grade pancreatic intraductal papillary mucinous neoplasms to invasive cancer

Abstract Intraductal papillary mucinous neoplasms (IPMN) is one of the known precancerous lesions. Patients’ prognosis is aggravated as IPMN transforms into invasive Pancreatic Ductal Adenocarcinoma (PDAC). The molecular mechanisms underlying this progression lack effective experimental models and urgently need to be elaborated. We performed spatial transcriptomics (ST) on fresh tissue samples from the same patient including normal pancreas, high-grade IPMN, and invasive PDAC, and described the step-by-step development of transcriptional landscape including clone evolution and adjacent TME feature variation. Our findings identified the master transcript factors and critical signaling pathways promoting IPMN progression to invasive PDAC. Additionally, both IPMN and PDAC harbored the ELF3, MYC, and KLF4 amplification. The Spatial CNV profile demonstrated significant heterogeneity among PDAC in their spatial distribution compared to IPMN, with seven distinct subclones showing diverse functions, such as hypoxia, oxidative phosphorylation, and epithelial-mesenchymal Transition. We observed a marked shift in the immune landscape, with the depletion of CD4+ T-cells and dendritic cells and an increase in immune-suppressive M2 macrophages in invasive PDAC, indicating a transition to an immune-evasive microenvironment. Additionally, cancer-associated fibroblasts (CAFs), particularly myofibroblastic CAFs, were enriched adjacent to invasive PDAC, suggesting their active role in tumor progression. By leveraging spatial transcriptomic analysis, our study provides comprehensive insights into the intricate molecular landscape that underlies the progression of IPMNs to invasive PDAC. These findings not only enhance our understanding of this complex process but also offer valuable knowledge for early diagnosis and intervention. Highlights Spatial CNV analysis reveals clonal evolution and distinct subclones in PDAC. Key drivers like ELF3, MYC, and KLF4 are amplified in both IPMN and invasive PDAC. Immune landscape shifts from pro-inflammatory in IPMN to immune-evasive in PDAC. Enrichment of myofibroblastic CAFs suggests their role in tumor progression Competing Interest Statement The authors have declared no competing interest.