Caroline Escoubas Lab

Microglia, the brain's resident immune cells, exist in multiple transcriptional states during development, though the functional significance of this diversity remains poorly understood. We previously identified a Type I interferon (IFN-I)-responsive microglial state in the developing cortex that engulfs whole neurons carrying DNA damage, a process required for normal cortical maturation and behavior. We found that double-stranded RNA serves as an endogenous signaling cue between neurons and microglia to mediate this effect. This raises the intriguing hypothesis that nucleic acids are actively regulated during development to modulate neural circuit development and behavior.

We are currently investigating how endogenous nucleic acids such as double-stranded RNA are produced and direct neuro-immune functions in brain development. We use genetically engineered mouse models to perturb components of nucleic acid sensing pathways to determine how they regulate microglial state, function, and distribution, and ultimately, circuit development. We also leverage primary neuron-microglia co-culture to investigate how neurons regulate the production of endogenous nucleic acids and how microglia sense and respond to these signals.

Pediatric brain tumors are increasingly understood as developmental diseases: they arise while the brain is actively growing and being remodeled by microglia, and they typically carry a far lower mutational burden than adult brain tumors. This raises the possibility that the tumor microenvironment, rather than tumor-intrinsic mutations alone, plays an outsized role in disease progression. Notably, several of the molecular cues tightly regulated during normal brain development, such as nucleic acids or interferons, are also dysregulated within pediatric brain tumors. We hypothesize that this overlap reflects a fundamental vulnerability of the developing brain that pediatric tumors exploit.

While immune cells have been studied as targets for cancer immunotherapy, the role of microglia in tumor initiation and progression remains largely unexplored, particularly in pediatric brain cancers. We are using single-cell and spatial transcriptomic data from patient tumors and relevant mouse models to define conserved and tumor-specific microglial states, focusing initially on diffuse midline glioma, a tumor with abundant immune infiltration and few effective treatment options. By pairing a computational approach with functional studies of microglia-tumor cell interactions in vitro and in vivo, we aim to determine whether tumors hijack the same molecular signals that guide microglia during healthy brain development, ultimately opening new opportunities for improving treatments and patient outcomes.