Acinar Metaplastic Cells Generate Semi-Homogeneous Niches and Interact With Immune Cells

BACKGROUND & AIMS: Metaplasia is the first stage in cell transformation that can lead to malignancy. Acinar metaplastic cells form premalignant lesions that have the potential to become invasive and develop into a deadly pancreatic ductal adenocarcinoma. We and others previously showed that acinar metaplastic cells are heterogeneous and include 7 distinct subtypes. The distribution of metaplastic cell types across lesions, their interactions with one another, and their crosstalk with stromal and immune cells remain largely unknown. METHODS: We performed single-cell RNA sequencing, spatial transcriptomics, and hematoxylin-eosin staining of mouse and human samples. RESULTS: We found a nonrandom distribution of metaplastic cells along the lesions, with cells of the same type tending to be close to each other, suggesting proliferation after defining cell identity. We also observed that metaplastic proliferating cells and senescent cells, as well as metaplastic tuft-like cells and metaplastic chief-like cells, frequently colocalize within the same lesions. We investigated the metaplastic cell types associated with higher-grade lesions and found increased expression of Muc4, Lcn2, and Cd274, highlighting genes that may drive the malignant process. In addition, we discovered niches that are highly enriched for specific metaplastic cell types and identified immune cells within these regions. We detected close interactions between metaplastic uncommitted cells and immunosuppressive neutrophils, as well as between metaplastic senescent cells and a subpopulation of macrophages. CONCLUSIONS: Our findings suggest that metaplastic cells can program immune cells in a specific manner at an early stage of cancer initiation to support an immunosuppressive microenvironment within defined niches.