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PROGRAM | Biological Sciences

Characterizing the Role of ADAM9 in Colorectal Cancer

By: Chamath Chandrasekera Chair: Shuo Wei


ADAMs are multidomain proteins with diverse biological functions including cell adhesion, fusion, migration, and proteolytic shedding. Hence, they participate in a variety of normal and pathological processes. In recent years ADAMs have been implicated in the initiation and progression of multiple tumors, and resistance to cancer treatments. This has prompted more detailed investigations into the mechanisms of these enzymes as well as the development of novel inhibitors against this group of enzymes.

Here I focus on ADAM9 which is a proteolytically active ADAM that plays diverse roles in many types of solid tumors. However, its role in colorectal cancer is not well known.  In Chapter 2 we show that ADAM9 is overexpressed in patient colorectal cancer tissue and that knockdown of ADAM9 inhibits colon cancer cell migration and invasion in vitro by reducing the activity of Akt which is antagonized by ephrin-Bs. Ephrin-Bs are ligands for EphB receptors which are the largest family of receptor tyrosine kinases. They are known to play roles in both tumor promotion and suppression. We showed previously that proteolysis of ephrin-B ligands by the disintegrin metalloproteinase ADAM13 is necessary for canonical Wnt signal activation and neural crest induction in Xenopus, but it was unclear if these mechanisms are conserved in mammals. Here, we report that mammalian ADAM9 cleaves ephrin-B1 and -B2 and can substitute for Xenopus ADAM13 to induce the neural crest.

Akt is a signaling node that activates multiple downstream pathways including the Wnt and mTOR pathways, both of which can promote CRC cell migration/invasion. Interestingly, knockdown of ADAM9 downregulates Wnt but has moderate effects on mTOR signaling in SW620 cells; in contrast, mTOR activity is suppressed while Wnt signaling remains unaffected in HCT116 cells. Our data suggest that mammalian ADAM9 cleaves ephrin-Bs to derepress Akt and promote CRC migration and invasion, but the signaling pathways downstream of Akt are differentially regulated by ADAM9 in different CRC cell lines, likely depending on their genetic backgrounds.

In Chapter 3 I validate the use of a biochemical assay and a cell-based activity assay to measure the activity of ADAM9 in vitro. I tested 4 previously published inhibitors but was unable to show adequate inhibition. With plans to test a compound library of over 1000 compounds for potential inhibitors, I developed an in-house baculovirus expression system for ADAM9. Recombinant ADAM9 has been successfully expressed and purified and characterization of this enzyme is currently underway. 

Chapter 4 highlights the effect of ADAM9 in glioma where I show that ADAM9 knockdown has similar effects in reducing glioma cell migration and invasion in vitro. The mechanism of ADAM9 in glioma may mimic the mechanism in colorectal cancer and the study of this is underway. The role of ADAM9 in promoting different cancers is increasingly relevant and the field would benefit from more investigation into the structure and inhibitor profile of ADAM9. The hope is that our study will lead to the discovery of novel inhibitors that can target this enzyme.

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