Abstract LB265: The spatial landscape of cancer hallmarks reveals patterns of tumor ecological dynamics and drug sensitivity

Abstract Tumors are dynamic ecosystems where interactions between cancer cells and the tumor microenvironment (TME) shape malignancy. Using spatial transcriptomics, we analyzed 63 untreated tumors from 10 cancer types to investigate the spatial distribution of 13 cancer hallmarks. Our findings reveal that hallmark activity is spatially organized, with distinct compartmentalization of hallmark phenotypes across neoplastic and TME regions. Hallmarks such as "Resisting Cell Death" and "Enabling Replicative Immortality" were enriched in cancer-dominant areas, while "Inducing Angiogenesis" and "Activating Invasion and Metastasis" were primarily localized to the TME. Genomic analysis showed that subclonal diversity influences hallmark specialization, with genetically distinct clones often occupying specific ecological niches. These insights suggest that hallmark activities are not uniformly distributed but instead reflect the interplay between genetic heterogeneity and tumor spatial organization. We further modeled the spatial interdependence of hallmarks between the neoplastic and TME compartments, demonstrating that hallmark activities are shaped by ecological dynamics across the tumor. For example, hallmarks such as "Sustaining Proliferative Signaling" in the TME interface strongly influenced cancer cell hallmark expression. Application of this framework to 33 bladder cancer patients from the DUTRENEO trial revealed correlations between hallmark spatial patterns and treatment response. Notably, differences in the spatial localization of "Inducing Angiogenesis" and "Resisting Cell Death" were linked to neoadjuvant chemotherapy and immunotherapy sensitivity. These findings underscore the importance of spatial hallmark distribution in determining drug efficacy and suggest that spatial hallmark signatures could serve as predictive biomarkers for personalized cancer therapy. Citation Format: Eduard Porta-Pardo, Mustafa Sibai, Sergi Cervilla, Daniela Grases, Manel Esteller. The spatial landscape of cancer hallmarks reveals patterns of tumor ecological dynamics and drug sensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB265.