Defining novel mechanisms of tumor progression and novel therapeutic targets for gastroenteropancreatic neuroendocrine tumors (GEP-NETs)
GEP-NETs are heterogeneous tumors for which therapeutic options are limited and must therefore be enlarged. Targeted therapies, and mainly everolimus-directed mTOR inhibition, constitute standard treatments for GEP-NETs of pancreatic origin. Nevertheless, the therapeutic benefits of everolimus have not been evaluated in the poorly-differentiated GEP neuroendocrine carcinomas (pdGEP-NECs) subgroup. By using a preclinical in vivo model, we demonstrated that mTOR inhibition could be considered as a therapeutic option for pdGEP-NECs. Then, a proteomic study highlighted novel proteins involved in GEP-NETs progression with all identified factors displaying function in cytoskeleton regulation. Among them, CRMP2 is a key member of class 3 semaphorin (sema3) signaling. An expression profile of sema3 revealed that sema3F expression was decreased in GEP-NETs. The re-expression of this protein in TNE-GEPs cellular models showed that sema3F is responsible of the reduction of cell viability and proliferation. In vivo, sema3F hampered tumor development. Further studies are thus needed to better understand the role of the sema3F signaling pathway in the progression of GEP-NETs