Inspired by evidence that TAMC programs can be reprogrammed, the patient received hydroxychloroquine as adjuvant therapy. This was associated with reduced peritoneal RG-like cells and increased cytotoxic CD8⁺ T cell recruitment/activation. 18/n

We validate the clinical relevance in a striking case of abdominal metastasis via VP shunt, where ascitic fluid was dominated by RG-like tumor cells and infiltrating myeloid cells that progress toward an immunosuppressive, complement-TAMC-like state. 17/n

This RG-like/complement-TAMCs ecosystem shares stress-, motility-, and immune-related gene signatures, suggesting a cooperative axis that supports invasion/adaptation. 16/n

Importantly, we discovered a third niche, stable during disease progression, enriched with stem-like states dominated by RG-like cells and complement-high TAMCs, displaying the highest proliferation + invasiveness (primarily driven by RG-like cells! not OPC-like).🤯 15/n

Importantly, despite changes in their proportions, both niches remain consistently present across patient samples, highlighting fundamental microenvironments that persist despite therapy-driven remodeling! 14/n

Both single-cell and spatial data confirmed that tumor-reactive regions align with high hypoxia/stress, while astro-microglial niches sit in lower-stress regions. 13/n

We characterize TAMCs' programs, defining both homeostatic and inflammatory microglia, as well as multiple programs linked to lipid metabolism, complement signaling, and immune suppression. 9/n

Using updated human developmental brain references, we refine malignant-state nomenclature and position tumor cells along an axis of (1) developmental mimicry ↔ (2) tumor-reactive, stress/TME-driven programs. 5/n

To tackle this, we built pHGGmap: a large, multimodal atlas integrating sc/snRNA-seq, snATAC, Multiome + spatial transcriptomics, across discovery + validation cohorts (over 800,000 analyzed cells from 136 patients). 4/n

I’m excited to finally share our research on pediatric high-grade gliomas (pHGG), the result of years of effort integrating single-cell and spatial datasets to offer a fresh perspective on their organization and potential treatment strategies doi.org/10.64898/202... 🧵👇🏼 1/n