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Integrated Methylation and Spatial Transcriptomic Profiling of Metaplastic Breast Cancer identifies putative master regulators of intratumoral heterogeneity

ABSTRACT: Metaplastic breast cancer (MpBC) is a rare and aggressive form of breast cancer. Characteristically heterogeneous, MpBC are defined by the presence of various morphological elements, typically biphasic, with epithelial (e.g. non-special type (NST), squamous) and mesenchymal (e.g. spindle, chondroid, osteoid) components. The established clonality of the different components, favours an evolution model encompassing either a multipotent progenitor, or a linear metaplastic conversion. Our study defines the micro-methylome and a spatial transcriptomic profile in MpBC, and identifies potential drivers associated with tumor heterogeneity that supports the conversion model of metaplasia and warrants further functional analysis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE278722 | GEO | 2025/08/12

REPOSITORIES: GEO

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Project description:Metaplastic breast cancer (MpBC) is a rare and aggressive form of breast cancer. Characteristically heterogeneous, MpBC are defined by the presence of various morphological elements, typically biphasic, with epithelial (e.g. non-special type (NST), squamous) and mesenchymal (e.g. spindle, chondroid, osteoid) components. The established clonality of the different components, favours an evolution model encompassing either a multipotent progenitor, or a linear metaplastic conversion. We performed methylation profiling to understand the nature of the different components, and to investigate their origins. The different morphologies demonstrated specific methylation profiles, with inter-patient clustering of common elements, rather than intra-patient clustering of distinct elements. While the malignant squamous components had a methylation profile consistent with normal squamous cells, chondroid regions were more like malignant chondroid tumours e.g. chondrosarcoma; indeed, this corresponds to the good and bad prognosis of squamous and chondroid MpBC phenotypes respectively. Our spatial transcriptomic approach, using 10X Genomics Visium and trajectory analysis evidenced that spindle cells form a transition between the originating carcinoma of non-special type (NST) and pleomorphic regions, with osteoid differentiation likely to be an end-stage fate of the chondroid growth pattern. This data lends itself to the conversion model of lineage differentiation. Considering the gene expression changes in more detail, we have also identified a series of master transcription factors likely to regulate these processes, and which are significantly associated with metaplastic-like features (basal/claudin-low; high grade; triple negative) in clinical data (METABRIC). Together, our study defines the micro-methylome and a spatial transcriptomic profile in MpBC, and identifies potential drivers associated with tumour heterogeneity that supports the conversion model of metaplasia and warrants further functional analysis.

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.

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Integrated Methylation and Spatial Transcriptomic Profiling of Metaplastic Breast Cancer identifies putative master regulators of intratumoral heterogeneity

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