Abstract 6238: Interactions between ploidy and resource availability shape clonal interference in glioblastoma

Whole-genome doubling (WGD) transforms a diploid cell into a tetraploid state, making it prone to genomic instability, aneuploidy, and malignancy. Tumors with evidence of past WGD events range from less than 10% in Non-Hodgkin’s Lymphoma to almost 60% in germ cell cancer. WGD confers advantages, including resistance to stressors, making it a powerful macroevolutionary force. Why, then, isn’t WGD a precursor for most cancers? In Glioblastoma (GBM), ∼86% of tumors lack evidence of WGD in their evolutionary history. We integrated a multi-modal dataset of 11 histopathology whole slide images (WSIs), 68 medical images, and whole-genome sequencing data (WGS) from six patient-matched primary and recurrent GBM. Three atlases were derived from FDG PET/MRI (glucose uptake), quantitative BOLD imaging (oxygenation), and magnetic resonance elastography (stiffness), capturing variability across brain regions and patient age. Using HATCHet, which infers clone-specific karyotypes from WGS, we quantified GBM clonal composition and its changes between surgeries. Chromosome 7 amplification and chromosome 10 loss were detected in at least one clone in all tumors. Genetic intra-tumor heterogeneity (coexistence of ≥2 clones) was found in 4/6 patients, with moderate to strong clonal changes between surgeries in all four. This data informed parameters governing how cells of variable (poly)aneuploidy respond to oxygen and glucose by dying (α_d, s_r), switching to glycolysis (O_th), or migrating (v_max). Two parameters significantly differed among patients: oxygen-dependent death constant α_d (ANOVA p = 1.7E-5) and oxygen level prompting a metabolic shift to glycolysis O_th (ANOVA p = 1.9E-4). Higher-ploidy GBMs showed elevated O_th values, and higher-ploidy clones within tumors had consistently higher O_th than coexisting lower-ploidy clones. Between surgeries, simulated tumors with distinct karyotype compositions progressed at different rates. Whether higher ploidy predicted fast recurrence was however a function of the tumor anatomic location, in line with the hypothesis that environments with limited resources are likely to exert selective pressure against WGD. Compared to intra-brain differences in resource supply, the differences observed between organs can be larger, providing an opportunity to further test this hypothesis. Indeed, the average ploidy of 20 different cancer types was positively correlated with the oxygen levels recorded in their respective organ of origin (Spearman r = 0.65, P = 0.002) and negatively correlated to the glucose uptake rates in the organ of origin (Spearman r = -0.70, P = 0.026). Overall, our findings suggest that metabolic substrate availability in the tissue micro-environment influences cell fate decisions based on karyotype, shaping GBM initiation and recurrence. Citation Format: Zuzanna Nowicka, Frederika Rentzeperis, Vural Tagal, Konstantin Maksin, Parag Katira, Noemi Andor. Interactions between ploidy and resource availability shape clonal interference in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6238.