Lysyl oxidase-like 3 is a novel druggable target in melanoma

Abstract

Lysyl oxidase-like 3 (LOXL3) is a member of the lysyl oxidase family comprising multifunctional enzymes with depicted roles in extracellular matrix maturation, epithelial to mesenchymal transition (EMT), development, differentiation and angiogenesis, as well as in distinct pathologies such as fibrosis and cancer 1-4. Extensive work by our lab and others has established the deregulation of lysyl oxidases in cancer and their status has been associated with patient outcome in specific neoplasias 1,2. Our previous studies identified human LOXL3 as a modulator of EMT and Snail1 functional activity 5 and we have recently unveiled an unexpected contribution of LOXL3 to melanoma pathogenesis 6. Our studies reveal a role for LOXL3 in melanoma biology since - Human melanoma cells are addicted to LOXL3 expression and LOXL3 knockdown halts cell proliferation and triggers apoptosis. - LOXL3 cooperates to malignant transformation and contributes to melanomagenesis. - LOXL3 binds to proteins that protect genome integrity while LOXL3 absence promotes a defective DNA damage checkpoint activation, deficient DNA repair and aberrant mitosis in melanoma cells. Based on these results, we have generated a genetically engineered mouse model with conditional deletion of Loxl3. This inducible Loxl3 knock-out mouse was crossed to an established melanoma genetic model that recapitulates the biology of melanoma initiation, progression and metastasis mimicking the human disease 7. Ongoing experiments show that, in the absence of Loxl3, the onset of nevi is delayed while overall survival of mice is increased compared to control animals. Moreover, metastatic burden is lower in the absence of Loxl3 confirming that Loxl3 plays an important role in melanoma pathogenesis in vivo. Our data reveal an unexpected role for LOXL3 in the control of genome stability and melanoma progression, exposing its potential as a novel therapeutic target in malignant melanoma, a very aggressive condition yet in need for more effective treatment options.