Semaphorin signalling controlling cancer cells and the tumour microenvirnoment.

4th December 2014.  
Luca Tamagnone, University of Torino – Candiolo Cancer Institute, IRCCS

The seminar will take place in the Division of Immunology and General Pathology of the Department of Molecular Medicine (C Golgi/L Spallanzani building) at 4.15 pm. The poster can be downloaded here.

Semaphorins are a large family of evolutionary conserved extracellular signals, controlling axonal and cell guidance during embryo development, as well as immune function, bone homeostasis, and cancer progression in the adult stage. We have previously identified semaphorin receptors in the families of Plexins and Neuropilins, and investigated various signaling cascades elicited by these signals in cancer cells and in cells of the tumor microenvironment. For instance, secreted and membrane-anchored semaphorins may use substancially different signaling mechanisms. Moreover, both plexins and neuropilins have been found to associate with tyrosine kinase receptors (such as VEGFR, Met, ErbB2, EGFR, etc) on the cell surface, and I will present evidences about the role of this mechanism in the context of cancer.

Selected references:

1)    Worzfeld T & Offermanns S. Semaphorins and plexins as therapeutic targets. Nat Rev Drug Discov. 13(8):603-21 (2014).
2)    Casazza A, et al. Impeding Macrophage Entry into Hypoxic Tumor Areas by Sema3A/Nrp1 Signaling Blockade Inhibits Angiogenesis and Restores Antitumor Immunity. Cancer Cell 24(6): 695-709 (2013).
3)    Tamagnone L. Emerging role of semaphorins as major regulatory signals and potential therapeutic targets in cancer. (2012) Cancer Cell 22(2):145-52.
4)    Rizzolio S et al. Neuropilin-1 dependent regulation of EGF-Receptor signaling. Cancer Res. 72: 5801-5811 (2012).
5)    Casazza A et al.. Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform. EMBO Mol Med. 4:234-50 (2012).
6)    Casazza A et al. Sema3E-PlexinD1 signaling drives cancer cell invasiveness and metastatic spreading in vivo. J. Clin. Invest. 120:2684-98 (2010).

Luca Tamagnone's research focuses on the regulation of cancer cell behavior by extracellular signals, in particular the semaphorins and their receptors. At the beginning of his career, he studied Met tyrosine kinase and its ligand HGF/SF with P Comoglio, in Torino. After accomplishing an M.D. in 1992, he moved to the lab of K Alitalo in Helsinki, where he learned molecular biology, and cloned novel genes encoding tyrosine kinases (such as RYK and BMX). Back in Italy, he started to work on a new family of orphan receptors, the Plexins, which were the topic of his PhD. thesis; in 1999 he published that plexin were receptors for the Semaphorins. As tenured Associate Professor at the University of Torino, and Young Investigator of the European Molecular Biology Organization (EMBO), in 2001 he started his own lab in the Institute for Cancer Research of Candiolo-Torino. Over the years, he focused on semaphorin/plexin activities in cancer cells, identifying fundamental signaling mechanisms and functional properties of these molecules. By exploiting experimental models in vivo in mice his group found that semaphorins and their receptors regulate multiple steps of cancer progression: from tumour growth, to angiogenesis, to the recruitment of tumor-associated macrophages and metastatic spreading, which makes them challenging targets for molecular therapy.

Image: Axon srouting, from G Lopez-Bendito, Instituto de Neurociencias de Alicante.








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