Loxl3 Promotes Melanoma Progression and Dissemination Influencing Cell Plasticity and Survival

Malignant melanoma is a highly aggressive tumor causing most skin cancer-related deaths. Understanding the fundamental mechanisms responsible for melanoma progression and therapeutic evasion is still an unmet need for melanoma patients. Progression of skin melanoma and its dissemination to local or distant organs relies on phenotypic plasticity of melanoma cells, orchestrated by EMT-TFs and microphthalmia-associated TF (MITF). Recently, melanoma phenotypic switching has been proposed to uphold context-dependent intermediate cell states benefitting malignancy. LOXL3 (lysyl oxidase-like 3) promotes EMT and has a key role in human melanoma cell survival and maintenance of genomic integrity. To further understand the role of Loxl3 in melanoma, we generated a conditional Loxl3-knockout (KO) melanoma mouse model in the context of BrafV600E-activating mutation and Pten loss. Melanocyte-Loxl3 deletion increased melanoma latency, decreased tumor growth, and reduced lymph node metastatic dissemination. Complementary in vitro and in vivo studies in mouse melanoma cells confirmed Loxl3’s contribution to melanoma progression and metastasis, in part by modulating phenotypic switching through Snail1 and Prrx1 EMT-TFs. Importantly, a novel LOXL3-SNAIL1-PRRX1 axis was identified in human melanoma, plausibly relevant to melanoma cellular plasticity. These data reinforced the value of LOXL3 as a therapeutic target in melanoma.
This research was funded by grants from the Spanish Ministry of Science and Innovation MCIN (SAF2016-76504-R to A.C. and F.P., PID2019-111052RB-100 to F.P., and PID2019–104644RBI00 to G.M.-B.), Instituto de Salud Carlos III (CIBERONC-CB16/12/00295 to A.C. and G.M.-B.), all of them partly supported by EU-FEDER funds, Worldwide Cancer Research UK (grant ref. 16-0295 to A.C., F.P., and P.G.S.), and FC AECC (Grupos Estables de Investigación 2018-AECC and PROYE19036MOR to G.M.-B., and 2015-AECC to À.F., GCB15152978SOEN). S.S.O. was supported by a 2019 AECC postdoctoral contract. A.V.-N. was supported by a FPI predoctoral fellowship from MCIN (BES-2017-081082). J.B.-T. was supported by a FPI fellowship associated with SAF2013-44739-R (A.C. and F.P.).