Spatially Resolved Opto-Omics Uncovers Functional Microglial Subtypes in Brain Metastasis

The tumor microenvironment plays an important role in brain metastasis. To investigate microglial subtypes in the developing metastatic tumor microenvironment in this issue of Cancer Research, Tsuji and colleagues pioneer a cutting-edge approach for mapping the transcriptional fate of live, spatially identified cells using a method they call "opto-omics." Using a mouse model that enables microglia-specific transgenic expression of a photoconvertible fluorescent protein, the authors profile disease-associated microglia in spatial proximity to disseminated tumor cells (DTC) through intracerebral windows installed in the mouse skull. Microglia that spatially migrate to DTCs are photoconverted, and transcriptional profiling of these microglia reveals an overall enrichment in inflammatory gene programs with five distinct subpopulations corresponding to biological processes such as antigen presentation, type II IFN response, phagocytosis, TGFβ signaling, and tissue repair. This article describes a strategy to modulate the relative abundance of individual microglial subpopulations through pharmacologic perturbation of specific pathways, such as TGFβ, or through genetic ablation of "don't eat me" signals to reprogram protumor microglia. By developing opto-omics and demonstrating its functional integration with single-cell transcriptomics, the authors present a versatile platform for phenotypic profiling that may be applied in numerous areas of research. See related article by Tsuji et al., p. 1414.