Single cell sequencing reveals the landscape of the brain metastatic microenvironment

Our analysis identifies intratumoral components that are predominantly tumor cells, fibroblasts, myeloid cells, stromal cells that express neural stem cell (NSC) markers, with minor populations of oligodendrocytes (oligo) and T cells. Different samples present diverse cell compositions, indicating the underlying cellular interactions that affect different cellular infiltration within TME. Importantly, we identify the tumor-associated fibroblasts in both in-house and external scRNA-seq datasets that 1) highly expresses type I collagen genes; 2) dominates the cell-cell interactions in TME through the type I collagen signaling axis; and 3) remodels the TME to a collagen-I-rich extracellular matrix (ECM) similar to the original TME at the primary sites. We also observe the M1 activation of the native microglial cells and the infiltrated macrophages, which may create a proinflammatory TME and be responsible for the high expression of collagen type I in fibroblasts. Moreover, the tumor cell-specific receptors are significantly associated with patients' survival in both brain metastasis and the native glioblastoma cases. Overall, our analyses identify the type I collagen secreting tumor-associated fibroblasts as a key mediator in metastatic brain tumors and reveal the involved tumor receptors associated with patients' survival. Our discoveries provide potential biomarkers for effective therapeutic targets and intervention strategies. Overall design: Using single-cell RNA sequencing, we have profiled five brain tumor tissue samples that are metastasis from breast and lung cancer.