Cancer genomes accumulate a wide variety of mutations. Next generation genome sequencing data provide an unparalleled depth of information about the changes that occur as a result of selective pressure during disease progression. At the same time, they pose a challenge in distinguishing “driver” mutations that are causally linked to disease from “passenger” mutations that may be present, but with limited impact on disease. Activating mutations in EGFRs and downstream effectors in the PI3K/AKT and MAPK signaling pathways have been recognized as driver mutations in human cancer. Understanding these modifications has a major impact in guiding therapeutic choice and in understanding the basis for clinical resistance to targeted therapies. However, much remains to be learned about other factors that may cooperate with important driver mutations to promote disease progression.
Drosophila provides a genetically tractable model in which to study oncogene cooperation because the signaling pathways involved in tumor formation and metastasis are well conserved from flies to humans). For example, a model based on expression of an oncogenic form of Ras was found to be insufficient to direct tumor formation and metastasis without additional mutations.
The researchers in this study show that bantam microRNA (miRNA) and its target, Socs36E, are cooperating factors in EGFR-driven tumorigenesis and metastasis in a Drosophila tumor model. In the past, bantam has been implicated in the control of cell proliferation and apoptosis during tissue growth and is a key effector of the growth-promoting activity of the Hippo signal transduction pathway. The bantam miRNA has also recently been identified as a target of the EGFR pathway that links EGFR and Hippo pathway signaling in growth control. We identified Socs36E as a target of bantam in growth control. The findings presented here show that SOCS36E and its human ortholog, SOCS5, behave as tumor suppressors.