Abstract
Abstract Understanding how radiotherapy induces metabolic reprogramming and reshapes the cytoarchitecture of the tumor microenvironment (TME) is essential for improving treatment outcomes and overcoming resistance. Despite its importance, no studies have used computational tools to quantitatively assess these cytoarchitectural rearrangements in the TME following radiotherapy. In previous work, we developed a quantitative method called “colocatome analysis,” a spatial -omic approach that catalogs statistically significant colocalizations between pairs of cell subpopulations or states. Through a normalization process, this method enables direct comparisons of spatial features across different conditions, including comparisons between in vitro models and tissue samples. We applied colocatome analysis to multiplexed immunofluorescence images of lung adenocarcinoma specimens, examining differences between naïve and recurrent tumors following radiotherapy using a panel of markers that represent primary tumor compartments (endothelial, malignant, fibroblast, and immune) and include markers for the hexosamine biosynthesis pathway (HBP), glycans, key metabolic enzymes, proliferation, cell death, DNA damage, hypoxia, and EMT. Our preliminary results indicate significant cytoarchitectural differences: tumors that recurred after radiotherapy exhibited a lower epithelial-to-mesenchymal cancer cell ratio and were enriched in FAP+ cancer-associated fibroblasts (CAFs). Although the overall proportions of macrophages and other immune cells remained consistent across samples, their spatial organization differed. In naïve tumors, immune cells were largely segregated from cancer cells, while recurrent tumors showed a more homogeneous mixture of cancer and immune cells. Additionally, CAFs were markedly increased in recurrent tumors. Lastly, cancer cells in naïve tumors displayed high levels of O-GlcNAc, which significantly decreased in recurrent tumors. These findings provide insights into the impact of metabolic reprogramming towards HBP in the TME and highlight its potential role in mediating radioresistance. Citation Format: Gina Bouchard.Spatiometabolic mapping of cytoarchitectural changes in lung adenocarcinoma following radiotherapy.[abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr P019
Published Version
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