Mure | Faculty Fellow Pilot Project

Project Title

Understanding the molecular mechanisms of LOXL2 in aggressive tumors

Project Leader

Minae Mure, Associate Professor, Department of Chemistry

Project Summary

Lysyl oxidase-like 2 (LOXL2) is a promising therapeutic target for various aggressive and metastatic cancers that pose serious threats to women’s health, as they are considered incurable without effective targeted therapy. The development of specific mechanism-based inhibitors of LOXL2 will be a new strategy for treating these cancers. There is an increasing body of evidence supporting the tight link between the overexpression of LOXL2 and tumor aggressiveness, as well as poor prognosis from extensive research on large-scale cohorts of human tumor samples. However, very little is known about the mechanisms by which LOXL2 contributes to these disease conditions, and how LOXL2 interacts with receptors, factors and/or substrates at the molecular level. In the study, we will identify active site residues that are essential for the amine oxidase activity of LOXL2 by evaluating the activity of mutants. We will define the modes of inhibition by small molecule inhibitors that are commonly used in in vitro and in vivo studies and identify the site(s) of modification (oxidative deamination) by LOXL2 in recently identified substrates by LC-MS/MS analysis. The results will be integrated into the molecular modeling study based on our 3D-modeled structure of the active form of LOXL2.We will also collaborate with experts at the core to evaluate published Big Data analytics suggesting the strong interaction of LOXL2 with TME, including ECM, EMT, vasculogenic mimicry, and premetastatic niches of aggressive tumors that significantly affect women’s health. Such collaboration would aid in identifying LOXL2 partner proteins to be evaluated by in vitro assays and the patterns of LOXL2-ligand complexes in Big Data to strengthen our future grant proposal.