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Single cell transcriptomes of pancreatic pre-invasive lesions and cancer reveal acinar metaplastic cells’ heterogeneity [MERFISH]

ABSTRACT: In this project, we utilized single-cell RNA sequencing (scRNA-seq) and MERFISH spatial transcriptomics to profile the development of pancreatic cancer in a mouse model, tracing its progression from the pre-invasive stage to full malignancy. By employing a reporter gene, we were able to dissect the heterogeneity of metaplastic acinar cells, identifying and profiling six distinct types and states of these cells. We validated their localization within pre-invasive lesions, assessed the heterogeneity across various lesions, and calculated the colocalization of different acinar metaplastic cells with stromal cells.

ORGANISM(S): Mus musculus synthetic construct

PROVIDER: GSE274617 | GEO | 2026/05/01

REPOSITORIES: GEO

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Project description:We used single-cell RNA sequencing to profile mouse pancreas across models of acute pancreatitis (AP), recurrent acute pancreatitis (RAP), chronic pancreatitis (CP), and oncogenic Kras-driven acute pancreatitis (K-AP, abbreviated APK). We captured both whole-pancreas cell suspensions and FACS-enriched mKate2+ epithelial populations from defined timepoints spanning early injury, recurrent damage, chronic inflammation, and Kras-driven precursor lesion formation. These data characterize acinar and epithelial plasticity and associated microenvironmental remodeling across pancreatitis and Kras-mediated disease initiation. BACKGROUND & AIMS: In response to injury, pancreatic acinar cells undergo acinar-to-ductal metaplasia (ADM), marked by loss of acinar identity and acquisition of ductal features. While ADM can resolve to support tissue repair, it may also persist and serve as a precursor to pancreatic cancer. Whether diverse pancreatic stressors drive a shared or context-specific ADM program remains unclear. We sought to comprehensively define metaplastic responses to clinically relevant exocrine pancreas diseases known to increase cancer risk. METHODS: We profiled ADM and the surrounding microenvironment across mouse models of exocrine disease—including acute, recurrent, and chronic pancreatitis, as well as in the setting of oncogenic Kras—capturing over 300,000 single cells. To enable high-quality transcriptomic profiling in enzyme-rich tissue, we leveraged FixNCut, a method that preserves RNA integrity in the exocrine pancreas. Findings were validated in human pancreas tissue using CosMx spatial transcriptomics. RESULTS: We identify a conserved acinar response across disease contexts that gives rise to previously unrecognized distinct metaplastic states, including a “gateway” ADM population that precedes more advanced metaplastic states marked by complete loss of acinar identity. In pancreatic intraepithelial neoplasia (PanIN) precancerous lesions, we detect classical-like and basal-like states, suggesting that pancreatic cancer subtypes are specified much earlier than previously appreciated. In Kras-mutant tissue, we identify a second wave of inflammation and the emergence of an immunosuppressive niche, coinciding with PanIN formation. CONCLUSIONS: Our findings define a conserved program of acinar plasticity across exocrine pancreas diseases. We further link unresolved ADM to immune remodeling during precursor lesion formation and observe the emergence of pancreatic cancer subtypes in early PanIN lesions.

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Single cell transcriptomes of pancreatic pre-invasive lesions and cancer reveal acinar metaplastic cells’ heterogeneity [MERFISH]

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