Abstract 7101: Remodeling of cancer cells by chemotherapy

Abstract Cisplatin is a commonly administrated chemotherapy drug for cancer treatment. Although the direct mechanism of cisplatin is largely well-defined, it is challenging to comprehensively assess its systemic effects. Cellular responses to perturbations are intricate processes involving modifications to protein complexes across diverse cellular compartments. Therefore, substantial research endeavors have been directed towards unraveling protein organization in cells. We recently built a multiscale integrated cell map, MuSIC, that combines fluorescence-stained images and interactions derived from affinity purification mass spectrometry to allow comprehensive characterization of cellular structure and functional networks of 5,254 proteins of the human bone osteosarcoma epithelial line (U2-OS). To exploit the biology of U2OS, we integrated dynamics into this map to determine the proteome reorganization upon cisplatin exposure. Thus, we developed a data-driven approach integrating high throughput size exclusion chromatography mass spectrometry (SEC-MS) data with large-scale cell maps built from static-state information to systematically map at all scales the remodeling of cell architecture in drug-treated cells. Here, we acquired drug-perturbed protein-protein interactions (PPIs) from the SEC-MS data by treating U2-OS with cisplatin. Integrating the differential interactions identified from SEC-MS PPIs with the scaffold large-scale hierarchy (MuSIC) allows retention of the upper cellular organization to systematically map drug impact on protein complexes in the cell. This pipeline serves as an explorative method to identify the drug-responsive organelles, alterations of hierarchical structures, and translocation of proteins. Apart from the well known alterations of DNA damage repair complexes, we also recapitulate remodeling in metabolism pathways, splicing, cAMP-dependent kinase activity, and histone modification. We identify 26 novel protein assemblies containing members that are previously associated with cisplatin biology. This pipeline exploits the potential of a well-established network by integrating the high throughput data modality, allowing for the screening of a range of chemical agents and stimuli to generate differential networks. Citation Format: Gege Qian, Leah Schaffer, Kyung-Mee Moon, Leonard Foster, Trey Ideker, Mengzhou Hu, Sahar Alkhairy, Emma Lundberg. Remodeling of cancer cells by chemotherapy [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 7101.