JAK/STAT pathway dysregulation in tumors: A Drosophila perspective

• JAK/STAT signaling is central to epithelial and hematopoietic tumors in Drosophila.
• Unpaired is ectopically induced by loss of distinct tumor suppressors.
• Ras and JAK/STAT pathways cooperate to induce metastatic tumors.
• Dominant-active JAK mutations cause melanotic tumors, a fly leukemia.
• Genetic screens have identified new pathway effectors in blood cell tumors.

Sustained activation of the JAK/STAT pathway is causal to human cancers. This pathway is less complex in Drosophila, and its dysregulation has been linked to several tumor models in this organism. Here, we discuss models of metastatic epithelial and hematopoietic tumors that are causally linked to dysregulation of JAK/STAT signaling in Drosophila. First, we focus on cancer models in imaginal discs where ectopic expression of the JAK/STAT pathway ligand Unpaired downstream of distinct tumor suppressors has emerged as an unexpected mediator of neoplastic transformation. We also discuss the collaboration between STAT and oncogenic Ras in epithelial transformation. Second, we examine hematopoietic tumors, where mutations that cause hyperactive JAK/STAT signaling are necessary and sufficient for “fly leukemia”. We highlight the important contributions that genetic screens in Drosophila have made to understanding the JAK/STAT pathway, its developmental roles, and how its function is co-opted during tumorigenesis.