Integrated profiling of metaplastic breast cancer identifies putative master regulators of intratumoral heterogeneity

Metaplastic breast cancer (MpBC) is defined by the presence of various morphological elements, typically biphasic, with epithelial (e.g. no-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 used methylation profiling and showed that different morphologies have specific methylation profiles. Furthermore, our spatial transcriptomic approach, using 10× Genomics Visium and trajectory analysis, evidenced that spindle cells form a transition between the originating carcinoma of no-special type (NST) and pleomorphic regions, with osteoid differentiation likely to be an end-stage fate of the chondroid growth pattern, supporting the conversion model of lineage differentiation. We have also identified a series of master transcription factors likely to regulate these processes, and are significantly associated with metaplastic-like clinical features. This data further supports the conversion model of metaplasia and warrants functional analysis.