Cell fate depends on genetic, epigenetic and environmental inputs that are interconnected, making it difficult to disentangle their respective contributions to cell fate decisions (1-3), and epigenetic reprogramming is a major contributor to tumor plasticity and adaptation (4-6). Although cancer initiation and progression are generally associated with the accumulation of somatic mutations (7,8), substantial epigenomic alterations underlie many aspects of tumorigenesis and cancer susceptibility

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... 9-18), suggesting that genetic mechanisms alone may not be sufficient to drive malignant transformations (19-23). However, whether purely non-genetic reprogramming mechanisms are sufficient to initiate tumorigenesis irrespective of mutations is unknown. Here, we show that a transient perturbation of transcriptional silencing mediated by Polycomb-Group proteins is sufficient to induce an irreversible switch to a cancer cell fate in Drosophila. This is linked to the irreversible derepression of genes that can drive tumorigenesis, including JNK and JAK-STAT signalling pathways and zfh1, the fly homolog of the ZEB1 oncogene, which we show to be a necessary driver of the cancer fate. These data show that a reversible perturbation of Polycomb-Group protein levels can induce cancer in the absence of driver mutations and suggest that this is achieved through epigenetic inheritance of altered cell fates.