Abstract 6543: A map of osteosarcoma cell architecture reveals convergence of pediatric cancer mutations on protein assemblies

Abstract Pediatric tumors are characterized by a low incidence of somatic mutations, which occur in different genomic patterns from adult cancers. For these reasons, interpreting the functional impact of mutations in pediatric cancer patients has remained difficult. One approach to interpreting rare coding mutations is to analyze the convergence of these mutations on larger structural and functional units, such as protein complexes, super assemblies, biomolecular condensates, and organelles. Towards this aim, we created a cancer cell map in the osteosarcoma cell line based on proteome-wide integration of protein interactions and immunofluorescent imaging in U-2 OS pediatric bone cancer cells. This multiscale integrated cell map of U-2 OS cell organizes 5,254 proteins into 270 protein assemblies. Using this multiscale cell map, we analyze 772 genomes from 18 cancer types reported in the DKFZ pan-pediatric cancer study to identify 25 protein assemblies in the map under mutational pressure. This analysis reveals mutated protein assemblies involved with chromatin maintenance and remodeling as well as cell integrity and mobility. For example, we identify a Collagen Biosynthesis and Remodeling Complex, as mutated in 9 cancer types and 15 patients in the dataset, indicating extracellular matrix remodeling is associated with pediatric cancer progression. We also identify a putative biological condensate, which we call the Nuclear Transcription Suppression Complex (NTSC). This protein assembly is found mutated in 20 patients across 10 cancer types, implicating intrinsically disordered proteins in development of pediatric cancer. Overall, this work illustrates how a global multiscale map of cell architecture enables a mechanistic understanding of clinical patient genomes. Citation Format: Mengzhou Hu, Leah V. Schaffer, Edward L. Huttlin, Gege Qian, Andrew Latham, Abantika Pal, Laura Pontano Vaites, Trang Le, Yue Qin, Christopher Churas, Dexter Pratt, Robin Bachelder, Peter Zage, Ignacia Echeverria, Andrej Šali, J. Wade Harper, Steven P. Gygi, Emma Lundberg, Trey Ideker. A map of osteosarcoma cell architecture reveals convergence of pediatric cancer mutations on protein assemblies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6543.