Fanconi Anemia Pathway Activation Converts Oncogene-Induced Senescence into a Pro-Tumorigenic State

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.