Xianjue Ma

Lineage-specific genes are widespread and have been implicated as phenotypic innovation inducers ¹ , but how they acquire complex developmental functions remains poorly understood. Ant queens and workers develop dramatically different organ sizes from identical genomes under juvenile hormone (JH) control ² , yet the molecular effectors translating JH signalling into caste-specific organ growth remain unknown. Here we identify torch , a Hymenoptera-restricted gene, as the most consistently gyne-biased and JH-responsive gene across 68 ant species. Knockdown of torch in virgin queens of Monomorium pharaonis produces a worker-like, multi-organ growth-restricted phenotype. Mechanistically, torch harbours an E-box-like motif activated by the JH receptor Gce–Tai and acts as a GA-repeat-binding transcription factor that regulates Hippo signalling, the deeply conserved organ-size control pathway in animals. Expressing torch heterologously in mice and a growth-restricted Drosophila background shows that the gene retained its general growth-promoting activity across more than 700 million years of animal evolution in lineages that lack the gene, establishing that its function is mediated through conserved rather than ant-specific machinery. A lineage-specific gene can therefore acquire complex morphogenetic function by co-opting ancient organ-size circuitry, providing a general route by which novel genes can drive phenotypic innovation.

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.

Tumor-suppressive cell competition (TSCC) is an evolutionarily conserved process that safeguards tissue integrity by selectively eliminating less-fit, precancerous cells. While bioelectric regulation via plasma membrane potential (Vₘ) is emerging as a key modulator of cellular fitness, its mechanistic role in TSCC remains underexplored. Here, we combine Drosophila genetics, single-cell RNA sequencing, and mammalian co-culture models to demonstrate that Vₘ depolarization acts as a critical driver of TSCC through Hedgehog signaling. In Drosophila eye epithelia, scribble-deficient (scrib-/-) “loser” clones exhibit mitochondrial respiratory chain defects, leading to reduced ATP synthesis and subsequent plasma membrane depolarization. This depolarization stabilizes Smoothened at the membrane, aberrantly activating Hh signaling and triggering the elimination of scrib-/- clones. Strikingly, this mechanism is conserved in mammalian epithelia: Scrib-depleted Madin-Darby Canine Kidney (MDCK) cells display Vₘ depolarization- dependent elimination via Hh pathway activation. Together, our work advances the understanding of bioelectricity in cancer surveillance and provides a mechanistic framework for targeting membrane potential in cancer prevention therapies that exploit cell competition.

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 Ras ^V12 -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-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 involving coordinated JNK, NF-κB/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.

Tumor heterogeneity, a hallmark of cancer, frequently leads to treatment failure and relapse. However, the intricate communication between various cell types within the tumor microenvironment and their roles in tumor progression in vivo remain poorly understood. Here we establish a novel tumor heterogeneity model in the Drosophila larval eye disc epithelium and dissect the in vivo mechanisms by combining sophisticated genetics with single-cell RNA sequencing. We found that mutation of the tricellular junction protein M6 in cells surrounding RasV12 benign tumors promotes their malignant transformation. Mechanistically, early RasV12//M6−/− tumors secrete Pvf1, which activates the Pvr receptor on hemocytes, facilitating their recruitment to the tumor site. These tumor-associated hemocytes secrete the Spätzle (Spz) ligand to activate the Toll receptor within the RasV12 tumors. This enhanced activation of the Toll pathway synergizes with RasV12 to promote malignant transformation through the JNK-Hippo signaling cascade. In summary, our study elucidates the complex interplay between genetically distinct oncogenic cells and between tumors and hemocytes, highlighting how hemocytes exploit the ancient innate immune system to coordinate tumor heterogeneity and drive tumor progression.