Abstract
Although RAS family genes play essential roles in tumorigenesis, effective treatments targeting RAS-related tumors are lacking, partly because of an incomplete understanding of the complex signaling crosstalk within RAS-related tumors. Here, we performed a large-scale genetic screen in Drosophila eye imaginal discs and identified Misshapen (Msn) as a tumor suppressor that synergizes with oncogenic Ras (RasV12) to induce c-Jun N-terminal kinase (JNK) activation and Hippo inactivation, then subsequently leads to tumor overgrowth and invasion. Moreover, ectopic Msn expression activates Hippo signaling pathway and suppresses Hippo signaling disruption-induced overgrowth. Importantly, we further found that Msn acts downstream of protocadherin Fat (Ft) to regulate Hippo signaling. Finally, we identified msn as a Yki/Sd target gene that regulates Hippo pathway in a negative feedback manner. Together, our findings identified Msn as a tumor suppressor and provide a novel insight into RAS-related tumorigenesis that may be relevant to human cancer biology.
Highlights
Our research shows that ectopic Msn overexpression induced mild Jun N-terminal kinase (JNK) activation (Figure 3A,B), whereas loss of msn alone had no significant change on puc transcription (Figure 1O), another canonical JNK pathway target [25]
The powerful genetic tools established in Drosophila, especially the mosaic analysis with a repressible cell marker (MARCM) system [52,53], make it possible to perform large-scale genetic screens aimed at identifying novel tumor suppressor genes in vivo [12,16,22]
We conducted an ethyl methanesulphonate (EMS)-induced unbiased modified genetic screen and identified misshapen (CG16973) as a tumor suppressor that synergizes with RasV12 to drive tumor overgrowth by inactivating Hippo signaling in Drosophila (Figure S5)
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The genetic screens in Drosophila have identified that the disruption of cell polarity genes (scrib, dlg, lgl) collaborate with oncogenic Ras (RasV12 ) or Notch to promote tumor overgrowth and invasion [12,13]. These established tumor models and genetic tools make it feasible to conduct large-scale genetic screens in Drosophila to dissect the mechanisms of RAS-related cooperative oncogenesis. Both c-Jun N-terminal kinase (JNK) and Hippo signaling pathways have been established in tumorigenesis. These findings uncovered Msn as a novel regulator of RAS-related cooperative oncogenesis, and provided a potential therapeutic target for RAS-related tumors
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