Probe and Target Lysyl oxidases (LOXs) in Cancer

PROJECT SUMMARY We work at the interface of chemistry and biology. Our research aims to understand how protein post- translational modifications (PTMs) and the enzymes involved contribute to cancer signaling and immune regulation, and how these PTMs, enzymes, enzymatic reactions, and related cellular processes can be exploited for targeted therapy. One of the PTMs that we are specifically focusing on involves protein crosslinking mediated by Lysyl Oxidase (LOX) family enzymes. LOXs, including LOX and four LOX-like proteins (LOXL1-4), are copper- and lysine tyrosylquinone (LTQ)-dependent amine oxidases. They catalyze the oxidative deamination of lysine residues on proteins, leading to the production of highly reactive aldehydes. These aldehydes form cross- linkages essential for the structural integrity of collagens and elastin within the extracellular matrix (ECM). While these processes are vital for tissue development, excessive LOX activity is linked to fibrotic and musculoskeletal diseases and is implicated in nearly all cancer types. LOXs are believed to promote malignant transformation by increasing ECM component secretion, stabilization, and crosslinking, thereby inhibiting drug and nutrient diffusion, and effector immune cell infiltration. High LOX expression in pre-malignant tissues and primary tumors correlates with increased tumor incidence, invasiveness, and poor patient outcomes. LOXs are significantly upregulated in a subset of solid tumors resistant to chemotherapy, radiotherapy, and immunotherapy, highlighting their crucial role in cancer pathophysiology and treatment resistance. Despite their importance, significant research gaps remain: 1) the identification of LOX substrates is limited due to a lack of technologies for profiling LOX substrate specificity and real-time activity in vivo; 2) there is minimal exploration of LOX functions in cancer progression beyond ECM remodeling; and 3) there is a scarcity of research on developing selective and effective LOX-targeting strategies, crucial for improving therapeutic efficacy and safety in cancer treatment. Our research aims to address these gaps by developing enabling technologies and novel inhibitors or probes to thoroughly investigate LOXs, exploring their biological functions and assessing their therapeutic potential in combination therapy. This initiative, spearheading advancements in technology development, biological study, and therapeutic intervention, is poised to establish a robust foundation for our laboratory's research endeavors for the foreseeable future.