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bioRxiv · 10.1101/2025.10.20.683390

Cross-Species Insights from ART-D to Uncover Evolutionarily Conserved Oncogenic Mechanisms

Guo, Y.·Zheng, J.·Wu, Y.·Zhao, K.·Lv, D.·Liu, W.·Wang, M.·Lu, J.·Xu, W.·Wang, X.·Ma, X.
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Abstract

Cancer arises from oncogenic clones, yet the dynamic mechanisms governing 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 through ten genetically defined RasV12-driven models. By integrating longitudinal phenotypic profiling, we define three conserved stages of tumor development--initiation, promotion, and progression--distinguished by dynamic changes in tumor burden and tumor-induced cachexia. Transcriptomic dynamics reveal stage-specific signaling rewiring: early tumorigenesis is marked by co-activation of JAK/STAT, NF-{kappa}B/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 involving coordinated JNK, NF-{kappa}B/Toll, Notch, and Hippo signaling that is functionally validated across species. ART-D provides a transformative resource that bridges Drosophila genetics and human cancer biology, offering a framework for decoding conserved oncogenic principles and enabling precision targeting of stage-specific vulnerabilities in RAS-driven cancers.

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Guo, Y., Zheng, J., Wu, Y., Zhao, K., Lv, D., Liu, W., Wang, M., Lu, J., Xu, W., Wang, X., Ma, X.. 2025-10-20. Cross-Species Insights from ART-D to Uncover Evolutionarily Conserved Oncogenic Mechanisms. https://doi.org/10.1101/2025.10.20.683390

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