Molecular pathology of intraductal papillary mucinous neoplasms of the pancreas: current understanding and perspectives on malignant progression - review

Sep 23, 2026

Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are established cystic precursor lesions to pancreatic ductal adenocarcinoma (PDAC), a cancer with a poor prognosis. Because IPMNs are often detectable by imaging, they provide a valuable opportunity for earlier intervention before invasive carcinoma develops. Although clinical visibility is high, molecular mechanisms of IPMN initiation and malignant progression were historically incomplete. Recent advances in next-generation sequencing and multi-omics approaches, including mass spectrometry and single-cell/spatial transcriptomics, have clarified genetic, transcriptomic, proteomic, metabolic, microbiome, and tumor microenvironment changes, informing mechanisms and perspectives.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

Early detection and precursor biology (PanIN vs IPMN)

Molecular pathology and multi-omics progress

Genomics and next-generation sequencing

Genetically engineered mouse models

Single-cell and spatial transcriptomics

J Gastroenterol (2026) 61:909–924 [https://doi.org/10.1007/s00535-025-02328-7](https://doi.org/10.1007/s00535-025-02328-7) REVIEW Molecular pathology of intraductal papillary mucinous neoplasms of the pancreas: current understanding and perspectiveson malignant progression Yuki Makino1 · Kohki Oyama2 · Akiko Sagara2 · Fredrik Ivar Thege3 · Anirban Maitra2 Received: 24 October 2025 / Accepted: 14 November 2025 / Published online: 26 November 2025 © The Author(s) 2025 Abstract Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are bona fide cystic precursor lesions to pancreatic ductal adenocarcinoma (PDAC), which is the cancer type with the most dismal prognosis. Since IPMNs are detectable by imaging, they offer a rare window of opportunity for early intervention for PDAC development. Despite their clinical visibility, the molecular pathogenesis of IPMNs remained incompletely understood, and no effective non-surgical therapeutic strategies have been established to date. In the past few decades, however, substantial progress has been made in elucidating their molecular pathology. Next-generation sequencing technologies demonstrated the comprehensive genetic mutation profile of IPMNs in the early 2010s. Elucidation of these mutation profiles enabled the establishment of genetically engineered mouse models, successfully recapitulating the natural development of human IPMNs and their progression to invasive cancer. Rapid evolution of “omics” technologies in recent years has facilitated the application of mass spectrometry, single-cell sequencing and spatial transcriptomics to IPMNs, significantly advancing our understanding of their pathophysiology. These techniques elucidated the changes in transcriptome, proteome, metabolome, microbiome, and tumor microenvironment associated with IPMN development and progression. This review summarizes current insights into * Yuki Makino [ymakino@gh.med.osaka-u.ac.jp](ymakino@gh.med.osaka-u.ac.jp) 1 Department of Gastroenterology and Hepatology, The University of Osaka Graduate School of Medicine, Suita, Osaka, Japan 2 Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY, USA 3 Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA the molecular and cellular landscapes of IPMN tumorigenesis, with particular emphasis on the mechanisms driving malignant progression. Keywords IPMN · Pancreatic cancer · Molecular pathology · Multi-omics Introduction Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with a steadily increasing incidence worldwide [1–3] . Despite advances in imaging and treatment modalities, its prognosis remains extremely poor, with a dismal 5-year survival rate of less than 10%. Globally, pancreatic cancer currently ranks among the highest causes of cancer-related mortality, and in the United States, it is projected to become the second leading cause of cancer death by 2030 [4]. This dire outcome is largely attributable to the fact that most patients are diagnosed at an advanced stage, when the disease has already progressed and surgical resection, the only potentially curative treatment, is no longer feasible. However, when detected and surgically resected at an early stage, this otherwise deadly disease can still be curable. Therefore, early detection and therapeutic intervention are essential for overcoming PDAC [5]. The key to this lies in the fact that pancreatic cancer arises from precursor lesions [1, 6, 7] . Two major precursors have been identified: pancreatic intraepithelial neoplasias (PanINs) and intraductal papillary mucinous neoplasms (IPMNs) . PanINs are microscopic lesions that cannot be detected by conventional imaging techniques and are typically found only in histological specimens. In contrast, IPMNs are macroscopic cystic lesions which can be detected through radiologic imaging such as MRI or CT. This fundamental dif

FAQs

Why are pancreatic IPMNs important for preventing PDAC?

IPMNs are cystic precursor lesions that can be detected by imaging, enabling potential diagnosis and treatment before progression to invasive pancreatic ductal adenocarcinoma.

What changed in the early 2010s that advanced understanding of IPMN biology?

Next-generation sequencing enabled comprehensive genomic mutation profiling, which supported the development of genetically engineered mouse models that recapitulate human IPMN development and progression.

What additional insights do multi-omics methods provide for IPMN progression?

Mass spectrometry, single-cell sequencing, and spatial transcriptomics reveal coordinated changes across transcriptome, proteome, metabolome, microbiome, and the tumor microenvironment that accompany IPMN development and malignant progression.

Sep 23, 2026

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