A tumor-suppressive role of the PRC1 Polycomb epigenetic complex in the maintenance of adult Drosophila intestinal stem cell identity

Chromatin modulators, like Polycomb group proteins, are key epigenetic regulators of gene expression and are frequently mutated in cancers. In adult stem cells, epigenetic regulation maintains their identity and controls their differentiation during homeostasis or aging, but its direct role in tumorigenesis remains unclear. This work explores the function of Polycomb Repressive Complex 1 (PRC1) in adultDrosophilaintestinal stem cells (ISCs). Disrupting core PRC1 components in ISCs induces the formation of small cell clusters devoid of intestinal markers, a novel phenotype linked to premature mortality under stress. Notably, transient PRC1 loss is sufficient for cluster formation. These clusters overproliferate and exhibit immortality in serial transplantations, leading to their designation as tumor-initiating intestinal cells (TIICs). While JAK/STAT signaling promotes TIIC formation, the TOLL/IMD immune pathways restrict their expansion independently of cell death. Altogether, our results highlight PRC1 as an epigenetic tumor suppressor in adult intestinal stem cells.