Hormone therapy resistance and the ensuing aggressive tumor progression present a significant clinical challenge. However, the mechanisms underlying the induction of tumor malignancy upon inhibition of steroid hormone signaling remain poorly understood. Here, we demonstrate that Drosophila malignant epithelial tumors show a similar reduction in ecdysone signaling, the main steroid hormone pathway. Our analysis of ecdysone-induced downstream targets reveals that overexpression of the nuclear receptor E75, particularly facilitates the malignant transformation of benign tumors. Genome-wide DNA binding profiles and biochemistry data reveal that E75 not only binds to the transcription factors of both Hippo and Notch pathways, but also exhibits widespread co-binding to their target genes, thus contributing to tumor malignancy. We further validated these findings by demonstrating that depletion of NR1D2 , the mammalian homolog of E75, inhibits the activation of Hippo and Notch target genes, impeding glioblastoma progression. Together, our study unveils a novel mechanism by which hormone inhibition promotes tumor malignancy, and describes an evolutionarily conserved role of the oncogene E75/NR1D2 in integration of Hippo and Notch pathway activity during tumor progression.

Interorgan communication is vital for tissue homeostasis and health in multicellular organisms, and its disruption can lead to diseases such as cancer. Adipose tissue acts as a key endocrine center, secreting cytokines that influence remote organs. Despite clear links between obesity and increased cancer risk, the underlying mechanisms are unclear. Here, utilizing a Drosophila genetic model combining Gal4-UAS and QF-QUAS tissue-specific transgene expression systems, we reveal that adipose-secreted Spz5 ligand promotes distal epithelial tumor overgrowth and invasion. Mechanistically, Spz5 binds to tumor cell Toll-6 receptors, triggering the degradation of the endocytic adaptor protein AP-2α via Mib1-mediated ubiquitination. Consequently, impaired endocytosis leads to Smoothened (Smo) accumulation on the cell membrane and subsequent activation of the Hedgehog (Hh) pathway. This abnormal Hh activation synergizes with the oncogenic Yorkie (Yki) to drive tumor growth and invasion. Furthermore, tumor-derived Unpaired ligands (Upds) activate the JAK-STAT pathway in the fat bodies, which leads to Hippo pathway-dependent upregulation of spz5 expression. Thus, our study provides insights into the complex regulatory mechanisms by which systemic interorgan communication influences tumor progression.

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.

Nuclear receptors orchestrate diverse biological processes through ligand-dependent transcriptional control, yet how competing family members balance oncogenic signaling to maintain tissue homeostasis remains poorly understood. Here, we uncover an evolutionarily conserved antagonism between nuclear receptors that directly controls tumor suppression through coordinated repression of the Hippo and Notch pathways. We identify Hr3 in Drosophila and its mammalian ortholog RORA as potent tumor suppressors that functionally oppose the oncogenic nuclear receptor E75/NR1D2. Using Drosophila genetic models and MARCM clonal analysis, we demonstrate that Hr3 suppresses tissue overgrowth, blocks invasion, and promotes apoptosis across multiple neoplastic contexts. Genome-wide CUT&Tag profiling reveals that Hr3 directly occupies regulatory elements of key Hippo and Notch target genes, with a remarkable 50% overlap with E75 binding sites, suggesting competitive antagonism. Mechanistically, Hr3 physically associates with core transcriptional machinery of both pathways, including Yorkie, Scalloped, Suppressor of Hairless, and Notch intracellular domain (NICD), to repress oncogenic gene expression programs and counteract E75-driven activation. Moreover, this regulatory axis is conserved in human cancer, where RORA overexpression suppresses glioblastoma cell proliferation, migration, and colony formation in a similar mechanism. Our findings establish nuclear receptor competition as a fundamental mechanism governing growth control and reveal therapeutic opportunities for targeting oncogenic transcriptional networks through endogenous regulatory circuits.