Abstract
Simple SummaryMalignant melanoma is the most lethal skin cancer due to its aggressive clinical behavior and therapeutic resistance. A comprehensive knowledge of the molecular mechanisms underlying melanoma progression is urgently needed to improve the survival of melanoma patients. Phenotypic plasticity of melanoma cells has emerged as a key process in melanomagenesis and therapy resistance. This phenotypic plasticity is sustained by an epithelial-to-mesenchymal (EMT)-like program that favors multiple intermediate states and allows adaptation to changing microenvironments along melanoma progression. Given the essential role of lysyl oxidase-like 3 (LOXL3) in human melanoma cell survival and its contribution to EMT, we generated mice with conditional melanocyte-specific targeting of Loxl3, concomitant to Braf activation and Pten deletion. Our results supported a key role of Loxl3 for melanoma progression, metastatic dissemination, and genomic stability, and supported its contribution to melanoma phenotypic plasticity by modulating the expression of several EMT transcription factors (EMT-TFs).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.
Highlights
Malignant melanoma is a highly aggressive tumor that accounts for only about 1% of skin cancers but causes most skin cancer deaths, and its incidence has risen rapidly over the last 50 years [1]
Administration of 4-HT resulted in the activation of the conditionally active CreERT2, which was expressed in melanocytes driving the expression of constitutively active BrafV600E and concomitant inactivation of Pten and Loxl3 gene expression (Figure 1C)
Administration of 4-HT resulted in the activation of the conditionally active CreERT2, which was expressed in melanocytes driving the expression of constitutively active BrafV600E and concomitant inactivation of Pten7 oafn2d2 Loxl3 gene expression (Figure 1C)
Summary
Malignant melanoma is a highly aggressive tumor that accounts for only about 1% of skin cancers but causes most skin cancer deaths, and its incidence has risen rapidly over the last 50 years [1]. Cutaneous melanoma is a highly heterogeneous disease that can be subtyped based on patterns of exposure to UV radiation, clinical and histopathological characteristics, and somatic mutations. These include oncogenic mutations in cell cycle regulators (CDKN2A) and members of the MAPK (mainly NRAS or BRAF) and PI3K/AKT pathways (PTEN) [4]. The development of targeted inhibitors against MEK and BRAF represented a milestone in melanoma therapy, but patients eventually relapse due to acquired resistance mechanisms [5]. Immunotherapy drugs, including cytokines and immune checkpoint inhibitors, have emerged recently as first-line treatment, alone or in combined therapies, in most melanoma patients [5,6,7]. Most patients still present disease progression within 5 years [8]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
