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<p>Cancer arises from oncogenic clones, yet the dynamic mechanisms driving their stepwise evolution toward malignancy remain incompletely understood. Here, we establish the Atlas of <i>Ras</i>-driven Tumors in <i>Drosophila</i> (ART-D), a systematic, cross-species platform that dissects the molecular and phenotypic trajectories of tumorigenesis across ten genetically defined <i>Ras</i><sup><i>V12</i></sup>-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 <i>Drosophila</i> genetics and human cancer biology, offering a robust framework for decoding conserved oncogenic principles and identifying of stage-specific vulnerabilities in <i>RAS</i>-driven cancers.</p>

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Cross-species insights from ART-D to uncover evolutionarily conserved oncogenic mechanisms

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月14日

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  • Yifan Guo,
  • Jiadong Zheng,
  • Yixin Wu,
  • Kun Zhao,
  • Dian Lv,
  • Wenhan Liu,
  • Mengling Wang,
  • Jin-Yu Lu,
  • Wenyan Xu,
  • Xianping Wang,
  • Xianjue Ma

摘要

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 RasV12-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.