Abstract B040: Uncovering senescence-driven pathways in diffuse midline glioma progression and treatment resistance

Abstract Diffuse midline gliomas (DMGs) are universally fatal pediatric brain tumors with a median survival of just 11 months. Despite radiation therapy offering temporary benefit, there are no effective long-term treatments, and targeted therapies have shown minimal impact. The infiltrative nature of DMGs, combined with their critical brainstem location, underscores the urgent need to identify novel mechanisms driving tumor progression and resistance. Cellular senescence is a state of permanent cell-cycle arrest induced by stress and has traditionally been viewed as tumor-suppressive. However, recent evidence in adult cancers implicates senescent cells as active contributors to tumor growth, treatment resistance, and relapse through the secretion of pro-tumorigenic factors known as the senescence-associated secretory phenotype (SASP). While senescence has emerged as a hallmark of cancer in adults, its role in pediatric tumors such as DMGs remains largely unexplored. Using single-cell RNA sequencing of treatment-naïve DMG specimens, we identified rare populations of senescent glioma cells and microglia that would be undetectable using conventional approaches. Computational analyses revealed predicted paracrine interactions between senescent and non-senescent cells including pathways previously linked to tumor invasiveness and resistance. This study aims to define how senescent cells and their secretory programs shape the tumor microenvironment, promote DMG progression, and contribute to therapy resistance. By elucidating these mechanisms, we hope to uncover new therapeutic vulnerabilities in DMGs and expand our broader understanding of senescence as a driver of malignancy in pediatric cancers. Citation Format: Timothy H. Chang, Alexander Nassar, Ria Kedia, Shriya M. Rangaswamy, Claudia Kleinman, Pratiti Bandopadhayay. Uncovering senescence-driven pathways in diffuse midline glioma progression and treatment resistance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2):Abstract nr B040.