My laboratory studies the way that normal mechanisms of development and neural plasticity are subverted or hijacked in the context of brain cancer. One interaction that we’ve been quite focussed on is understanding how neuronal activity, which normally regulates the proliferation of glial precursor cells that are important in the developing childhood brain as well as in mechanisms of ongoing neural plasticity in adulthood, how neuronal activity similarly influences the proliferation and ultimately the growth of high grade gliomas, both in childhood for cancers such as diffuse intrinsic pontine glioma but also in adulthood with respect to high grade gliomas like glioblastoma.
What we have found is that neuronal activity, like the normal counterpart, very dramatically influences the proliferation of malignant glial cells. Digging into the mechanism we’ve uncovered that there are at least a couple of activity-regulated secreted factors that seem to be very important for activity regulated growth of gliomas. One of them is a well-studied activity regulated neurotrophin called brain derived neurotrophic factor and the other one that we uncovered was really unexpected and not known to be a growth factor at all. It’s a synaptic protein called neuroligin 3 which normally functions as a synaptic adhesion molecule in normal synapses that form between neurons and other neurons as well as between neurons and some subtypes of glial cells. We find that neuroligin 3 is cleaved and secreted in an activity dependent way and then it very powerfully promotes glioma growth. Not only does it promote growth but unexpectedly we found that when we place gliomas in a brain microenvironment that lacks neuroligin 3 that the gliomas really fail to grow, underscoring a fundamental role of this molecule in glioma progression.
We identified the enzyme that’s responsible for release of neuroligin 3 into the tumour microenvironment and find that by blocking that enzyme, an enzyme called ADAM10, that we can slow the growth of high grade gliomas. So this is an exciting new angle that we’re hoping to translate for therapy.
We’re just at the tip of the iceberg as we begin to understand how the really powerful growth environment of the nervous system regulates brain cancer growth. There’s a lot more work to do.