TAMI-39. INTEGRATION OF SPATIALLY RESOLVED TRANSCRIPTOMICS AND METABOLOMICS UNCOVERS HYPOXIA-DRIVEN ACCUMULATION OF GENOMIC INSTABILITIES IN HUMAN GLIOMA
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Titel:
TAMI-39. INTEGRATION OF SPATIALLY RESOLVED TRANSCRIPTOMICS AND METABOLOMICS UNCOVERS HYPOXIA-DRIVEN ACCUMULATION OF GENOMIC INSTABILITIES IN HUMAN GLIOMA
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<jats:title>Abstract</jats:title>
<jats:p>High-dimensional technologies have provided insights into transcriptional heterogeneity and dynamic plasticity which are hallmarks of brain tumors. Although scRNA-seq recovers the diversity of transcriptional states, their spatial context within the neuronal environment has remained unexplored. Here, we integrated spatially resolved transcriptomics and metabolomics to characterize the glioma landscape at multiple molecular levels. We integrated spatial transcriptomics (10X Visium, n= 28) and metabolomics (MALDI, n= 6) from primary and recurrent glioblastoma patients. Unsupervised cluster analysis and pattern recognition uncovered 5 spatially distinct transcriptional programs, shared across patients. These included three cell-specific developmental stages largely reflecting those that are part of recently suggested models. By integrating metabolome data, we identified an additional program encompassing reactive responses to hypoxia. Areas of hypoxic response were negatively correlated with proliferation (R2= -0.34, p&lt; 0.001) and significantly enriched for gene expression signatures from the S-phase (p&lt; 0.001). Modeling of transient spatial gradients using vector field predictions showed opposing vector directions of hypoxia response and migratory capacity, underpinning the “go-or-growth” theory, where cells either proliferate or migrate. Inferred copy-number alterations (CNA) revealed a significant increase in genomic instability, highly correlated to hypoxia response (R2= 0.78, p&lt; 0.001). Near necrotic areas, we observed a significant accumulation of CNAs while proliferation was inhibited, and cells remained in the S-phase. We validated this hypothesis of hypoxia-driven accumulation of CNAs by chronic hypoxia cultures of primary patient-derived cell lines. A gain of chromosomal instability after long-term hypoxia was observed, suggesting that hypoxic areas in glioblastoma function as bioreactors for genomic instability. Our findings elucidate the evolution of resistant subclones in glioblastoma. They provide novel insights into the dynamic regulation and interaction between host and tumor and cast a new light on hypoxic and necrotic areas, which may represent the source of the heterogeneous and resistant nature of glioblastomas.</jats:p>