Oral Presentation 14th International Biennial Conference on Metastasis Research 2012

A furin resistant form of semaphorin-3E as a potential treatment for metastatic disease (#39)

Gera Neufeld 1 , Andrea Casazza 2 , Boaz Kigel 1 , Massimiliano Mazzone 3 , Luca Tamagnone 2
  1. Technion, Israel Institute of Technology, Haifa, Israel
  2. Institute for Cancer Research and Treatment (IRCC), University of Torino, Torino, Italy
  3. Vesalius Research Center, VIB, Leuven, Belgium

Secreted semaphorin 3E (Sema3E) promotes cancer cell invasiveness and metastatic spreading. The pro-metastatic activity of Sema3E is due to its proteolytic fragment p61, which is capable of trans-activating the oncogenic tyrosine kinase ErbB2 that associates with the Sema3E receptor PlexinD1 in cancer cells. Here, we show that a mutated, uncleavable variant of Sema3E (Uncl-Sema3E) binds to PlexinD1 like p61-Sema3E, but does not promote the association of PlexinD1 with ErbB2 nor activates the ensuing signaling cascade leading to metastatic spreading. Furthermore, Uncl-Sema3E competes with endogenous p61-Sema3E produced by tumour cells, thereby hampering their metastatic ability. Uncl-Sema3E also acts independently as a potent anti-angiogenic factor. It activates a PlexinD1-mediated signaling cascade in endothelial cells that leads to the inhibition of adhesion to extracellular matrix, directional migration and cell survival. The putative therapeutic potential of Uncl- Sema3E was validated in multiple orthotopic or spontaneous tumour models in-vivo, where either local or systemic delivery of Uncl-Sema3E-reduced angiogenesis, growth and metastasis, even in the case of tumours refractory to treatment with a soluble vascular endothelial growth factor trap. In summary, we conclude that Uncl-Sema3E is a novel inhibitor of tumour angiogenesis and growth that concomitantly hampers metastatic spreading.