Gege Qian

PhD Candidate<br>University of California, San Diego

Remodeling of Cancer Cell Architecture by Chemotherapy

How chemotherapy reshapes tumor cells—and how these changes influence outcomes such as drug resistance—remains largely unclear. Here, we present a multimodal, global characterization of tumor subcellular organization and its reorganization by chemotherapy. We use self-supervised learning to encode protein coordinates across four orthogonal data modalities: proteome-wide size-exclusion chromatography fractionation (before and after treatment with cisplatin or vorinostat), native-state immunofluorescence imaging, affinity purification, and primary sequence information covering 7,579 proteins. This integrated map resolves 174 subcellular components, spanning molecular assemblies from protein complexes to organelles across a size range of ~10–9 to 10–5 nm. 58 components undergo significant remodeling upon treatment, recapitulating known mechanisms of action and revealing previously unrecognized alterations in pathways such as cytoskeletal organization and metabolic rewiring. We systematically validate these “chemotherapy-response assemblies” using genome-wide CRISPR knockout drug-sensitivity profiling, identifying which assemblies confer drug sensitivity versus resistance. Chemotherapy-remodeled components serve as convergence points for cancer mutations that predict therapeutic response—including those involved in homologous recombination repair, chromatin remodeling, and double-strand break repair.