Intraductal Papillary Mucinous Neoplasm Cellular Plasticity is Linked with Repeat Element Dysregulation

Area of Science:

• Pancreatic oncology
• Molecular pathology
• Spatial transcriptomics

Background:

• Intraductal papillary mucinous neoplasms (IPMNs) are preinvasive pancreatic lesions with varying progression risk to invasive cancer.
• Aberrant repetitive element expression is linked to cell state changes in pancreatic cancer.

Purpose of the Study:

• To investigate the relationship between IPMN histologic subtypes, repeat element dysregulation, and molecular profiles using spatial transcriptomics.
• To understand the cell populations within IPMN and their molecular characteristics.

Main Methods:

• Whole transcriptome spatial analysis (GeoMx) and single-cell spatial molecular imaging (CosMx) were performed on 52 IPMN lesions.
• Customized repeat element probes (LINE1, HSATII, HERVK, HERVH) were utilized for both GeoMx and CosMx analyses.
• Single-cell transcriptional trajectory analysis was employed to map cellular relationships.

Main Results:

• Distinct IPMN subtypes (pancreaticobiliary, intestinal, gastric) showed enrichment for specific epithelial types and immune infiltrates.
• High levels of repeat RNAs were observed across all IPMN phenotypes, with enrichment in high-grade dysplasia.
• Transcriptional trajectory analysis revealed a progression from gastric-type towards intestinal and pancreaticobiliary phenotypes, associated with increased dysplasia and repeat RNA expression.

Conclusions:

• Spatial transcriptomics identified a molecular continuum among IPMN subtypes, supporting a common gastric-type origin.
• Cell state plasticity in IPMN is associated with repeat element expression, suggesting its potential as a biomarker for disease progression.
• Repeat RNA expression, alongside other transcriptional markers, could aid in monitoring IPMN progression.