P04.12.A MULTI-OMICS INTEGRATION IN POST-SURGERY RESIDUAL TUMOR UNVEILS INTENSE MICROENVIRONMENT RESHAPING

Abstract BACKGROUND Glioblastoma (GB), the most aggressive and lethal primary brain tumor, remains a formidable challenge, with a median survival of approximately 8 months despite current standard-of-care treatments, which typically involve surgical resection followed by concurrent chemoradiation. While the effects of adjuvant therapies on GB progression have been extensively investigated, the direct impact of surgery itself on tumor behavior remains poorly understood. This study aims to elucidate the role of surgical resection in shaping the microenvironment via multi-omics integration. MATERIAL AND METHODS We developed a syngeneic neurosurgical mouse model. Implantations of GB cell lines followed by size-matched surgical resection were performed to mimic human GB resection. Residual tumors were then collected one day after surgery to capture the early effects of surgical damage on the tumor ecosystem. The robustness of this model facilitated the generation of a comprehensive multi-omics dataset delineating postsurgical molecular alterations in both GB cells and their microenvironment. This dataset encompassed proteomic, phosphoproteomic, and single-cell RNA-sequencing data. RESULTS The integration of these datasets using both data-driven and prior knowledge-based approaches shed light on the complex molecular pathways underlying the response of residual tumors to resection. HIF1a, JUN, and SP1 emerged from this analysis as critical drivers of molecular response to surgery. Finally, using single-cell resolution from the RNA-seq data, we delineated the contribution of each cell type to overall changes. This methodology led us to identify hypoxic macrophages as a central communication hub driving both tumor microenvironment reshaping and residual tumor plasticity after surgery. CONCLUSION In conclusion, multi-omics study of the postsurgical effects on residual GBM cells and the microenvironment allowed us to discover new potential vulnerabilities in an unexplored phase of tumor progression. This may allow for the development of novel therapeutic strategies aimed at reducing post-surgery GBM aggressiveness and sensitizing it to subsequent therapies.