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Abstract Cancer arises from oncogenic clones, yet the dynamic mechanisms driving their stepwise evolution toward malignancy remain incompletely understood. Here, we establish the Atlas of Ras -driven Tumors in Drosophila (ART-D), a systematic, cross-species platform that dissects the molecular and phenotypic trajectories of tumorigenesis across ten genetically defined Ras V12 -driven models. By integrating longitudinal phenotypic profiling, we define three conserved stages of tumor development—initiation, promotion, and progression—distinguished by distinct shifts in tumor burden and tumor-induced cachexia. Transcriptomic analysis reveals stage-specific signaling rewiring: early tumorigenesis is characterized by co-activation of JAK/STAT, NF-κB/Toll, and MAPK pathways, whereas malignant progression is driven by Notch hyperactivation and Hippo pathway inactivation. Through integrative multi-omics and machine learning, we uncover an evolutionarily conserved pathogenic network coordinating JNK, NF-κB/Toll, Notch, and Hippo signaling, which we functionally validate across species. ART-D serves as a transformative resource bridging Drosophila genetics and human cancer biology, offering a robust framework for decoding conserved oncogenic principles and identifying of stage-specific vulnerabilities in RAS -driven cancers.
Guo et al. (Thu,) studied this question.