Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms Reveals Divergent Indolent and Malignant States

Date:	May 1, 2025
PMID:	39969959
Category:	N/A
Authors:	Matthew K Iyer, Ashley A Fletcher, Jude Ogechukwu Okoye, Chanjuan Shi, Fengming Chen, Elishama N Kanu, Austin M Eckhoff, Matthew Bao, Marina Pasca di Magliano, Timothy L Frankel, Arul M Chinnaiyan, Daniel P Nussbaum, Peter J Allen
Abstract:

Purpose: Intraductal papillary mucinous neoplasms (IPMN) occur in 5% to 10% of the population, but only a small minority progress to pancreatic ductal adenocarcinoma (PDAC). The lack of accurate predictors of high-risk disease leads to both unnecessary operations for indolent neoplasms and missed diagnoses of PDAC. Digital spatial RNA profiling (DSP-RNA) provides an opportunity to define and associate transcriptomic states with cancer risk.

Experimental design: We performed whole-transcriptome DSP-RNA profiling on 10 IPMN specimens encompassing the spectrum of dysplastic changes from normal duct to cancer. Epithelial regions within each tissue were annotated as normal duct, low-grade dysplasia, high-grade dysplasia, or invasive carcinoma. The resulting digital gene expression data were analyzed with R/Bioconductor.

Results: Our analysis uncovered three distinct epithelial transcriptomic states-"normal-like" (cNL), "low risk" (cLR), and "high risk" (cHR)-which were significantly associated with pathologic grade. Furthermore, the three states were significantly correlated with the exocrine, classical, and basal-like molecular subtypes described in PDAC. Specifically, exocrine function diminished in cHR, classical activation distinguished neoplasia (cLR and cHR) from cNL, and basal-like genes were specifically upregulated in cHR. Intriguingly, markers of cHR were detected in normal duct and low-grade dysplasia regions from specimens with PDAC but not from specimens containing only low-grade IPMN.

Conclusions: DSP-RNA of IPMN revealed low-risk (indolent) and high-risk (malignant) expression programs that correlated with the activity of exocrine and basal-like PDAC signatures, respectively, and distinguished pathologically low-grade specimens from malignant specimens. These findings contextualize IPMN pathogenesis and have the potential to improve risk stratification.

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Acknowledgements:

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, or the National Institute of Health.

The Translational and Basic Science Research in Early Lesions (TBEL) Research Consortia is supported and funded by grants from the National Cancer Institute and the National Institutes of Health under the following award numbers:

Project Number:	Awardee Organization
U54CA274374	Fred Hutchinson Cancer Center
U54CA274375	Houston Methodist Research Institute
U54CA274370	Johns Hopkins University
U54CA274371	UT MD Anderson Cancer Center
U54CA274367	Vanderbilt University Medical Center