Project description:Metaplastic breast carcinoma (MpBC) typically consists of carcinoma of no special type (NST) with various metaplastic components. The intracase transcriptomic alterations between metaplastic components and paired NST components, which are critical for understanding the pathogenesis underlying the metaplastic processes, remain unclear. Herein, 59 NST components and paired metaplastic components (spindle sarcomatous [SPS], matrix-producing, rhabdomyoid [RHA], and squamous carcinomatous [SQC] components) were microdissected from specimens obtained from 27 patients with MpBC for gene expression profiling. Hierarchical clustering and principal component analysis revealed a heterogeneous gene expression profile (GEP) corresponding to the NST components, but the GEP of metaplastic components exhibited subtype dependence. Compared with the paired NST components, the SPS components demonstrated the upregulation of genes related to stem cells and epithelial–mesenchymal transition, and displayed enrichment in claudin-low and macrophage signatures. Despite certain overlap in the enriched functions and signatures between the RHA and SPS components, the specific differentially expressed genes differed. We observed the RHA-specific upregulation of genes associated with vascular endothelial growth factor signaling. The chondroid matrix-producing components demonstrated the upregulation of hypoxia-related genes and the downregulation of the immune-related MHC2 signature and the TIGIT gene. In the SQC components, TGF-β and genes associated with cell adhesion were upregulated. The differentially expressed genes among metaplastic components in the 22 MpBC cases with one or predominantly one metaplastic component clustered paired NST samples into clusters with correlation with their associated metaplastic types. These genes could be used to separate the 31 metaplastic components according to respective metaplastic types with an accuracy of 74.2%, suggesting that intrinsic signatures of NST may determine paired metaplastic type. The EMT activity and stem cell traits in the NST components were correlated with specimens displaying lymph node metastasis. In summary, we presented the distinct transcriptomic alterations underlying metaplasia into specific metaplastic components in MpBCs.

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.

Dataset Information

Acute metaplastic injury of wild-type and Ifnar1-/-mice.

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