Early neoplastic lesions of the pancreas: initiation, progression, and opportunities for precancer interception
Brian A. Pedro, Laura D. Wood
Brian A. Pedro, Laura D. Wood
Published July 15, 2025
Citation Information: J Clin Invest. 2025;135(14):e191937. https://doi.org/10.1172/JCI191937.
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Review Series

Early neoplastic lesions of the pancreas: initiation, progression, and opportunities for precancer interception

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is known to progress from one of two main precursor lesions: pancreatic intraepithelial neoplasia (PanIN) or intraductal papillary mucinous neoplasm (IPMN). The poor survival rates for patients with PDAC, even those diagnosed with localized disease, highlight the need for pancreatic cancer interception at the precursor stage. Although their basic biological drivers are well characterized, practical strategies for PanIN and IPMN interception remain elusive due to difficulties with detection, risk stratification, and low-morbidity intervention. Recently, advances in liquid biopsy, spatial multiomics analysis, and machine learning technology have provided deeper understanding of the molecular landscapes underlying pancreatic precursor development and progression. In this Review, we outline the different histologic phenotypes, clinical characteristics, and neoplastic cell–intrinsic and –extrinsic drivers of PanINs and IPMNs, with particular focus on current and potential future opportunities for pancreatic precancer interception.

Authors

Brian A. Pedro, Laura D. Wood

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Figure 2

Drivers of pancreatic precancer progression.

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Drivers of pancreatic precancer progression. Schematic of known neoplast...
Schematic of known neoplastic cell–intrinsic and –extrinsic drivers of pancreatic precursor lesion progression from initiation to invasive disease, based on data from studies involving PanINs and IPMNs. (A) Early driver mutations are found in oncogenes (most commonly KRAS), while later driver mutations occur in tumor suppressor genes. Gene expression drivers of IPMN progression include decreased exocrine function and increased basal-like expression programs, with increased expression of specific genes such as TFF1 that are associated with PanIN progression. Tumor suppressor promoter hypermethylation is evident even in low-grade lesions, with gradual increases with increasing grade. Chromosomal instability is evident in high-grade lesions but shows an abrupt increase in invasive disease. (B) Immune surveillance decreases and the microenvironment becomes more immunosuppressive with increasing grade, including increased expression of checkpoint markers and higher density of regulatory T cells.