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

BACKGROUND

Intraductal papillary mucinous neoplasms (IPMNs) are known precancerous lesions whose malignant transformation to pancreatic ductal adenocarcinoma (PDAC) worsens prognosis. Current experimental models inadequately elucidate the molecular mechanisms driving this progression.

METHODS

We performed spatial transcriptomics (ST) on three fresh tissue samples from the same patient including normal pancreas, high-grade IPMN, and invasive PDAC. We used Spatial inferCNV to profile the evolutionary clone trajectory. We utilize SpaCET to identify the tumor region and adjacent tumor microenvironment (TME) feature variation, as well as its crosstalk between tumor cells by CellChat.

RESULTS

Our findings identified the master transcript factors and critical signaling pathways that might be involved in the progression of IPMN to invasive PDAC. Moreover, both IPMN and PDAC harbored the ELF3, MYC, and KLF4 amplification. We identified a significant heterogeneity among PDAC tissue with seven distinct subclones showing diverse functions, such as hypoxia, oxidative phosphorylation, and epithelial-mesenchymal Transition. Compared to IPMN, PDAC showed immune landscape remodeling: CD4+ T cells and dendritic cells depleted, while immunosuppressive M2 macrophages increased. In addition, cancer-associated fibroblasts (CAFs), particularly myofibroblastic CAFs, were enriched adjacent to invasive PDAC.

CONCLUSIONS

Our study integrates multiple computational approaches for spatial transcriptomics to identify ELF3/MYC/KLF4 amplifications during IPMN-to-PDAC progression, as well as 7 heterogeneous subclones with functions including hypoxia and EMT, alongside immune-stromal landscape remodeling and tumor-adjacent myofibroblastic CAF enrichment.