Marco Arese, Ph.D.
Associate Professor of Biochemistry
University of Torino, School of Medicine
Neuroligin: a novel modulator of cell transformation and cancer diffusion through nerves.
Neuroligin (NLGN) is a neuronal and tumoral adhesion protein that is a translational target of the mTOR (mechanistic target of rapamycin) kinase. mTOR plays a key role in tumorigenesis, but mTOR based therapies have had limited success, mainly because of evasive resistance and lack of predictive biomarkers of efficacy. Tumor-nerve interactions are a clinically significant but often underestimated way of cancer diffusion, including colorectal cancer (CRC). Tumor and nerve relations take place by Perineural Invasion (PNI), the invasion of nearby nerves by cancer cells, and neo-neurogenesis, or the stimulation of neurite outgrowth by the cancer through soluble signals. These obviously represent different aspects of a wide range of molecular interactions that are nevertheless poorly defined. Moreover, no specific therapy exists that will target tumor nerve interactions, so new molecular players and therapies are needed. Ultimately, finding novel proteins that provide insight into the tumorigenic properties of mTOR both in the tumor cell itself and in the microenvironment, as well as serving as predictive biomarkers, is paramount.
This laboratory has been working on the extra-neuronal activities of NLGN for the last ten years. Since 2013 we have focused on the following questions on the role of tumoral NLGN (mainly in CRC): (a) How does it impact tumor cell phenotypes? (b) Does it modulate PNI and neo-neurogenesis? (c) Does it influence the cancer response (growth/invasion/PNI) to mTOR inhibition? The results obtained to date show that NLGN inhibits tumor cell proliferation, anchorage independent growth and in vivo xenograft growth but promotes PNI. This last effect is completely abolished by drug-mediated blockade of mTOR.
Conclusions and perspectives:
If broadly confirmed, our data reveal NLGN as a double-faced cue (i.e. growth suppressing but pro- invasive) that is targeted by an existing anti-tumoral drug, hence carrying potential clinical implications. We now want to exploit the knowledge coming from the neuronal field, the large amount of reagents present in this laboratory, and in vitro and in vivo experimental settings (mouse xeno- and ortho- transplants) in order to fully answer the questions stated above.