Distinct tumor architectures and microenvironments for the initiation of breast cancer metastasis in the brain.

Brain metastasis, a serious complication of cancer, hinges on the initial survival, microenvironment adaptation, and outgrowth of disseminated cancer cells. To understand the early stages of brain colonization, we investigated two prevalent sources of cerebral relapse, triple-negative (TNBC) and HER2+ (HER2BC) breast cancers. Using mouse models and human tissue samples, we found that these tumor types colonize the brain, with a preference for distinctive tumor architectures, stromal interfaces, and autocrine programs. TNBC models tend to form perivascular sheaths with diffusive contact with astrocytes and microglia. In contrast, HER2BC models tend to form compact spheroids driven by autonomous tenascin C production, segregating stromal cells to the periphery. Single-cell transcriptomics of the tumor microenvironment revealed that these architectures evoke differential Alzheimer's disease-associated microglia (DAM) responses and engagement of the GAS6 receptor AXL. The spatial features of the two modes of brain colonization have relevance for leveraging the stroma to treat brain metastasis. [Display omitted] • Brain metastases initiate with distinct tumor architectures and stromal interfaces • Perivascular and spheroidal micrometastases elicit different microglial responses • Breast cancer cell-derived tenascin C (TNC) drives spheroidal colony growth • TNC triggers a disease-associated microglia state via type I interferon response Gan et al. reveal distinct tumor architectures, stromal interfaces, and tumor-intrinsic mechanisms that are preferentially adopted by prevalent brain metastases during the initiation of colonization. These findings highlight critical spatial and microenvironmental features that can be leveraged to target minimal residual disease in the brain. [ABSTRACT FROM AUTHOR]