Abstract B018: Decoding the evolutionary landscape of soft tissue sarcomas: From multiregion origins to therapy-driven adaptation

Abstract Soft tissue sarcomas (STS) represent a paradigm of cancer evolution, where spatial and temporal heterogeneity creates dynamic ecosystems that rapidly adapt to therapeutic pressures. Through multi-region multi-omics profiling of 45 patients across primary, irradiated, and recurrent tumors, we reconstructed evolutionary trajectories using an integrated analytical framework. DNA methylation (RRBS) was processed via Bismark, with CAMDAC deconvolution distinguishing cell type-specific signals from copy number alterations. Transcriptomic data were analyzed using Salmon and edgeR, while copy number landscapes were inferred through TitanCNA and InferCNV. Evolutionary dynamics were reconstructed using PRISM, enabling methylation-based phyloepigenome reconstruction to trace subclonal epigenetic evolution. Our analysis reveals that STS evolution follows a branching phylogenetic pattern, with early “trunk” alterations establishing the foundational epigenome and subsequent “branch” events driving radiation adaptation. PRISM-based methylation phylogenies demonstrated conserved evolutionary trajectories across patients, with epigenetic divergence increasing through treatment. At diagnosis, widespread methylome remodeling systematically rewires cellular identity, with convergent hypermethylation-mediated silencing of tumor suppressive networks (SMARCA4, DICER1, FOXO3) and hypomethylation-driven activation of oncogenic pathways (CCND1/2, CDK6). Across patients, these events were recurrent and enriched for functional gene expression changes, representing positive selection for survival advantages. Under radiotherapy selection pressure, the evolutionary dynamics shift from broad remodeling to targeted adaptation. The epigenome stabilizes, focusing on DNA repair (DDB2), stemness (ZBTB16), and proliferation (CCND1) pathways—evidence of directional selection for resistance mechanisms. Single-cell phylogenetics of >150,000 cells reveals that radiation selects for pre-existing subclones rather than generating novel populations, with overall ecosystem architecture maintained despite cellular turnover. Spatial-temporal mapping demonstrates that evolutionary trajectories vary dramatically both between patients and within individual tumors, generating multi-focal ecosystems where distinct subclones coexist, compete, and occasionally converge on shared adaptive solutions. This evolutionary framework explains radiotherapy resistance as the inevitable outcome of selection acting upon pre-existing heterogeneity. The convergent emergence of DNA repair enhancement, stem-like properties, and immunosuppressive niches across patients represents parallel evolution under common selective pressures. Together, these findings argue for the development of evolution-informed therapeutic strategies that anticipate and intercept adaptive trajectories, with the potential to overcome the formidable challenge of heterogeneity in treatment-resistant STS. Citation Format: Shaghayegh Soudi, Nadia Silvia, Ajay Subramanian, Serey Nouth, Faith Ryu, Taryn Kaneko, Christin New, Deborah Kenney, Raffi Avedian, Robert Steffner, David Mohler, Anusha Kalbasi, Matt van de Rijn, Gregory Charville, Everett Moding. Decoding the evolutionary landscape of soft tissue sarcomas: From multiregion origins to therapy-driven adaptation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr B018.