Background
The control of proliferation, survival and migration is commonly altered in tumor cells compared to normal counterparts. In particular, in invasion and metastasis, neoplastic cells evade their physiological niche and migrate through tissues while surviving apoptotic signals. This behaviour may depend on the functional regulation of cancer cells and on the expedience of cells in the tumor microenvironment. Semaphorins are a wide family of signals that we have recently implicated in these processes.
Achievements
We have identified a family of receptors for the Semaphorins, called Plexins, and studied the mechanisms through which these signals control cell migration, angiogenesis, tumor invasion and metastasis. We identified molecules associated with these receptors and required to mediate semaphorin functions, such as p190-RhoGAP and receptor tyrosine kinases Otk and Met. We have identified regulated genes downstream to semaphorin signals, such as interleukin-8, a cytokine that controls the tumor microenvironment. We have recently identified plexin mutations in human tumors of different origin. We recently demonstrated that Semaphorin 3E and its receptor PlexniD1 are major drivers of the metastatic spreading of cancer cells. Preliminary results indicate that semaphorin signals implicated in tumor progression may be targeted by blocking molecules, envisaging future validation of novel anti-cancer strategies in preclinical studies.
Goals
Major objectives of the group are to: (i) identify and characterize semaphorin signals controlling tumor progression, acting on cancer cells and/or on the microenvironment (e.g. angiogenesis, recruitment of bone marrow derived cells, etc.); (ii) elucidate the molecular mechanisms mediating semaphorin functions, including novel signal transducers associated with receptor complexes; (iii) validate molecular tools to specifically target these signalling pathways in order to interfere with tumor invasiveness and metastasis.
Internal collaborations
Lab of Molecular Biology: the role of PlexinB1 and Sema4D in cancer progression; Lab of Molecular Pharmacology: the role of CD151 and Sema3E in cancer progression; Lab of Oncogenomics: semaphorin-mediated regulation of gene expression in cancer cells; Division of Pathology: semaphorin and semaphorin receptor expression in human tumors; Division of Surgical Dermatology: semaphorin and semaphorin receptor expression in melanomas.
