The capacity of tumour cells to maintain continual overgrowth potential has been linked to the commandeering of normal self-renewal pathways. Using an epithelial cancer model in Drosophila melanogaster, we carried out an overexpression screen for oncogenes capable of cooperating with the loss of the epithelial apico-basal cell polarity regulator, scribbled (scrib), and identified the cell fate regulator, Abrupt, a BTB-zinc finger protein. Abrupt overexpression alone is insufficient to transform cells, but in cooperation with scrib loss of function, Abrupt promotes the formation of massive tumours in the eye/antennal disc. The steroid hormone receptor coactivator, Taiman (a homologue of SRC3/AIB1), is known to associate with Abrupt, and Taiman overexpression also drives tumour formation in cooperation with the loss of Scrib. Expression arrays and ChIP-Seq indicates that Abrupt overexpression represses a large number of genes, including steroid hormone-response genes and multiple cell fate regulators, thereby maintaining cells within an epithelial progenitor-like state. The progenitor-like state is characterised by the failure to express the conserved Eyes absent/Dachshund regulatory complex in the eye disc, and in the antennal disc by the failure to express cell fate regulators that define the temporal elaboration of the appendage along the proximo-distal axis downstream of Distalless. Loss of scrib promotes cooperation with Abrupt through impaired Hippo signalling, which is required and sufficient for cooperative overgrowth with Abrupt, and JNK (Jun kinase) signalling, which is required for tumour cell migration/invasion but not overgrowth. These results thus identify a novel cooperating oncogene, identify mammalian family members of which are also known oncogenes, and demonstrate that epithelial tumours in Drosophila can be characterised by the maintenance of a progenitor-like state.
Cancer is a multigenic process, involving cooperative interactions between oncogenes or tumour suppressors. In this study, in a genetic screen in the vinegar fly, Drosophila melanogaster, for genes that cooperate with a mutation in the cell polarity (shape) regulator, scribbled (scrib), we identify a novel cooperative oncogene, abrupt. Expression of abrupt in scrib mutant tissue in the developing eye/antennal epithelium results in overgrown invasive tumours. abrupt encodes a BTB-zinc finger transcription factor, which has homology to several cancer-causing proteins in humans, such as BCL6. Analysis of the Abrupt targets and misexpressed genes in abrupt expressing-tissue and abrupt-expressing scrib mutant tumours, revealed cell fate regulators as a major class of targets. Thus, our results reveal that deregulation of multiple cell fate factors by Abrupt expression in the context of polarity disruption is associated with a progenitor-like cell state and the formation of overgrown invasive tumours. Our findings suggest that defective polarity may also be a critical factor in BTB-zinc finger-driven human cancers, and warrants further investigation into this issue.