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Abstract Introduction: Children with H3K27-altered diffuse midline gliomas (DMG-H3K27a), have a 5-year survival rate of only 2% following diagnosis. While in-depth genomic characterization has been performed in DMG-H3K27a, very few druggable targets have been identified. A common feature of DMG-H3K27a is infiltration of microglia, macrophages, other myeloid cells, collectively referred to as GAMs. Cellular crosstalk between non-tumor and tumor cells in the tumor microenvironment (TME) can both promote and or inhibit tumor growth, thus representing an opportunity in the pursuit of novel therapeutics. We have recently determined that DMG-H3K27a tumor cells stimulate microglial secretion of pro-tumor growth factors. Hypothesis: Microglial-derived growth factors activate receptor tyrosine kinases (RTKs) via paracrine signaling in DMG-H3K27a. Methods: We used scRNA-seq and RNA-seq datasets and, in parallel, in vitro studies, such as co-culture studies, ELISA assays, western blotting, and growth assays to test our hypothesis. In addition, we are developing a mouse-human chimeric neutralizing antibodies of our top targets for in vivo studies. Preliminary Results: Microglial cells secrete growth factors into the TME, which promotes DMG-H3K27a cell proliferation and growth. Targeting growth factors with neutralizing antibodies attenuates glioma cell proliferation in co-culture studies. Conclusion: This research uncovers an important signaling network between GAMs and DMG-H3K27a that can be therapeutically targeted. Citation Format: Andrea Cruz, Brenden Johnson, Taylor Gatesman, Mathew Halbert, Suchet Taori, Baoli Hu, Gary Kohanbash, Ian F. Pollack, Sameer Agnihotri. The role of tumor microenvironment derived growth factors in pediatric brain tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB307.
Cruz et al. (Fri,) studied this question.