Distinct Transcriptional and Migratory Programs Are Associated with Vasculogenic Mimicry Heterogeneity in Triple-Negative Breast Cancer.

backgroundVasculogenic mimicry (VM) is a tumor-driven vascularization strategy in which aggressive cancer cells form perfusable, endothelium-independent channels that support tumor growth, metastasis, and therapy resistance. VM is prevalent in triple-negative breast cancer (TNBC), but within this group of tumors, VM heterogeneity is underexplored. Likewise, VM competence and its relationship to classical endothelial angiogenesis (EA) remain incompletely understood.

methodsHere, as a proof of concept, we combine functional analysis of three molecularly distinct TNBC cell lines with a panel-wide DepMap transcriptomic survey to characterize VM heterogeneity.

resultsUsing an in vitro tube formation assay, we show that the VM-competent TNBC cell lines MDA-MB-231 and MDA-MB-231-4175 form robust 3D vessel-like networks in a matrigel matrix, whereas the VM-incompetent line MDA-MB-468 does not. As a control, we use an immortalized endothelial cell line, 3B-11, that forms classical EA vessel-like networks. Moreover, we visualize VM (Laminin-5

conclusionsTogether, these findings indicate that VM is a distinct, heterogeneous, and therapy-relevant state in TNBC that complements classical angiogenesis. Finally, the mechanistic distinction between VM and EA programs made here will motivate future studies on dual-targeting strategies that inhibit both vascularization processes while also motivating future studies on VM for precision treatment in TNBC.