Brain metastases (BrMs) are a common occurrence in lung cancer with a dismal outcome. To understand the mechanism of metastasis to inform prognosis and treatment, here we analyze primary and metastasized tumor specimens from 44 non-small cell lung cancer patients by spatial RNA sequencing, affording a whole transcriptome map of metastasis resolved with morphological markers for the tumor core, tumor immune microenvironment (TIME), and tumor brain microenvironment (TBME). Our data indicate that the tumor microenvironment (TME) in the brain, including the TIME and TBME, undergoes extensive remodeling to create an immunosuppressive and fibrogenic niche for the BrMs. Specifically, the brain TME is characterized with reduced antigen presentation and B/T cell function, increased neutrophils and M2-type macrophages, immature microglia, and reactive astrocytes. Differential gene expression and network analysis identify fibrosis and immune regulation as the major functional modules disrupted in both the lung and brain TME. Besides providing systems-level insights into the mechanism of lung cancer brain metastasis, our study uncovers potential prognostic biomarkers and suggests that therapeutic strategies should be tailored to the immune and fibrosis status of the BrMs.

Src homology 3 (SH3) domains were initially characterized as a prevalent protein module that recognizes proline-rich sequences, in particular those containing a PxxP motif. Recent studies have shown that the specificity and cellular function of SH3 domains are far more diverse than previously appreciated. Despite lacking distinguishing features, the ligand-binding surface of an SH3 domain can be molded to accommodate a variety of peptide ligands. Moreover, certain SH3 domains are capable of using surfaces distinct from the canonical ligand-binding site to engage a peptide or protein. The identification of novel motifs and domains recognized by the SH3 domain greatly expands the ligand pool and cellular function for this family. However, this also imposes the question as to how the specificity of the hundreds of human SH3 domains is regulated in a cell to ensure their proper functions. Here we review literature on the specificity of SH3 domains, with an emphasis on the structural basis of ligand recognition, and discuss mechanisms employed by SH3 domain-containing proteins to execute defined cellular functions through highly regulated SH3-ligand interactions.

Engineered SH2 domains with high affinity for phosphorylated tyrosine inhibit cell signaling downstream of receptor tyrosine kinases.