Journal Article

Immunological and molecular insights into acinar-ductal metaplasia and atypical flat lesions as precursor lesions of pancreatic ductal adenocarcinoma

Haeberle, Lena, Goering, Wolfgang, Haensch, Sebastian, Yavas, Aslihan, Horny, Kai, Esposito, Irene, Boshoven, Leon, Schlensog, Martin

2026

Overview

Background Pancreatic ductal adenocarcinoma (PDAC) is known to develop through a stepwise progression from precursor lesions, such as pancreatic intraepithelial neoplasias (PanIN). An alternative carcinogenic pathway has been proposed via transformation of acinar cells, with development of acinar-ductal metaplasia (ADM) and atypical flat lesions (AFL). Defining the characteristics of PDAC precursors is crucial to better understand PDAC carcinogenesis. Methods 15 KC ( Ptf1a Cre/+ , Kras LSLG12D/+ ) and 15 KPC-like mice ( Ptf1a Cre/+ , Kras LSLG12D/+ , Trp53 LoxP/LoxP , referred as fKPC hereafter) were sacrificed at different time points. A meticulous morphological evaluation was performed to define different lesion types. Multiplex immunofluorescence staining was applied to define the characteristics of the immune and stromal microenvironment of the lesions. To investigate the association between the genetic alterations and the components of the microenvironment, all lesion types were subjected to next-generation sequencing (NGS) using a 20 genes-panel. Results AFL showed a trend towards a more intense immune cell infiltration compared to PanIN and ADM. AFL had higher number of CD4 + helper T cells, FOXP3 + regulatory T cells, and CD19 + B cells than all other analyzed lesions. They displayed more CD8 + cytotoxic T cells and FOXP3 + cells than PDAC, while peripheral and central PDAC tissues tended to be infiltrated by macrophages in higher frequency. In addition, αSMA-expressing myofibroblastic cancer-associated fibroblasts were tendentially more frequent in AFL than other lesions. PDAC appeared to have higher CXCL12 expression and more common CD109 + cells than other lesions. In NGS analysis, none of the lesions in fKPC mice revealed additional coding mutations, while the preneoplastic lesions in 7 KC mice showed variable coding alterations in 16 different genes. The most frequently affected genes were Arid1a , Rnf43 , and Pik3ca . PDAC precursors in KC mice showed more dense infiltration of adaptive immune cells than in fKPC mice, supporting the immunosuppressive role of Trp53 alterations. Conclusions Our study highlights the unique immunological and stromal features of AFL. Moreover, reinforcing their potential as precursor lesions, ADM and AFL exhibit variable alterations in the genes that have a critical role in PDAC carcinogenesis. Graphical Abstract

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V
• Subject: Acinar Cells - immunology / Acinar Cells - pathology / Adenocarcinoma / Animals / Apoptosis / B cells / Biomedical and Life Sciences / Biomedicine / Cancer Research / Carcinoma, Pancreatic Ductal - genetics / Carcinoma, Pancreatic Ductal - immunology / Carcinoma, Pancreatic Ductal - pathology / Development and progression / Fibroblasts / Growth factors / Humans / Immunology / Lasers / Lesions / Lymphocytes / Metaplasia - immunology / Metaplasia - pathology / Mice / Mutation / Oncology / Pancreatic cancer / Pancreatic Neoplasms - genetics / Pancreatic Neoplasms - immunology / Pancreatic Neoplasms - pathology / Precancerous Conditions - genetics / Precancerous Conditions - immunology / Precancerous Conditions - pathology / T cells / Tumor Microenvironment / Tumorigenesis / Tumors