ANTAGONISTIC COOPERATION BETWEEN NOTCH AND HEDGEHOG SIGNALING PATHWAYS IN CANCER

DOMINGUEZ M; DA ROS VG; GUTIERREZ PEREZ I; FERRES-MARCO D

Barcelona

Conferencia; 23rd EUROPEAN DROSOPHILA RESEARCH CONFERENCE; 2013

A fundamental and unresolved question in biology is what instructs cells to growth and when the proper size is attained to stopgrowing to commence terminal differentiation. These controls are not only relevant to size regulation but also, to cancer. Thegenetic control of organ and tissue growth is often linked to spatially confined domains known as organizers (conservedsignalling centres), established along the dorsal-ventral (DV) and anterior-posterior (AP) axes of the organ, often involvingmembers of the Notch (DV organizers) and Hedgehog (Hh) (AP organizers) families. The organizers emit signals that dictategrowth, cell fate specification and differentiation. However, how the distinct organizing signals received are integrated by cellswithin a growing organ remains a mystery. By studying how Delta-Notch signalling drives tumorigenesis, we identified theconserved microRNA miR-7 as a co-operative element in tumorigenesis mediated by Delta in the developing Drosophila eye. Wefound that the cooperation between the microRNA and Delta-Notch pathway converged on the silencing of two obligatory andfunctionally redundant Hedgehog receptors, interference hedgehog and brother of ihog. We then downregulated other hedgehogpathway genes via RNA interference or genetic mosaics and revealed a hitherto unsuspected tumour suppressor role forHedgehog signalling in the context of the oncogenic Notch pathway. Given the conservation of microRNA miR-7, as well as of theNotch and Hedgehog pathways, the conclusions we have drawn from these studies on Drosophila may be applicable to somehuman cancers.