GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE332nnn/GSE332838/primary200OKTranscriptomicsDrosophila melanogasterExpression profiling by arrayhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE332838GEOGSEfalseFanconi Anemia Pathway Activation Converts Oncogene-Induced Senescence into a Pro-Tumorigenic StateDNA repair pathways are canonically tumor-suppressive, yet emerging evidence suggests their upregulation can promote cancer progression, a paradox whose mechanisms remain poorly understood. Here, we report that activation of the Fanconi Anemia (FA) DNA repair pathway drives malignant tumor progression by reprogramming cellular senescence from a tumor-suppressive to a pro-tumorigenic state. Through an unbiased genetic screen in Drosophila, we identified that loss of Sras (homologous to human RCE1) cooperates with oncogenic RasV12 to induce slow-progressing yet highly malignant tumors. Bioinformatics analysis revealed marked upregulation of the FA pathway and Hippo signaling in these tumors. Genetic manipulation demonstrates that FA pathway activation is required for tumor growth and invasion. Mechanistically, we show that FA pathway upregulation enhances cellular senescence and triggers secretion of senescence-associated secretory phenotype (SASP) factors, particularly the cytokine Unpaired-1 (Upd1; IL-6 homolog), which in turn activates JAK-STAT signaling within tumor cells through an autocrine loop, thereby promoting tumor progression. Notably, p53 activation is dispensable for this pro-tumorigenic senescence program. FA pathway activation and its pro-tumorigenic function are conserved across multiple RasV12-driven malignant tumor models. Our findings reveal a previously unrecognized mechanism by which DNA repair machinery is co-opted to convert oncogene-induced senescence into a tumor-promoting state, with broad implications for understanding cancer progression and developing therapies targeting Ras-driven malignancies.2026/05/31GSE332838GSM9754119GSM9754118GSM9754120GSM9754122GSM97541211322332838Drosophila melanogaster