RESUMEN
The upregulation of the adaptor protein NUMB triggers melanocytic differentiation from multipotent skin stem cells, which share many properties with aggressive melanoma cells. Although NUMB acts as a tumor suppressor in various human cancer types, little is known about its role in melanoma. In this study, we investigated the role of NUMB in melanoma progression and its regulatory mechanism. Analysis of The Cancer Genome Atlas melanoma datasets revealed that high NUMB expression in melanoma tissues correlates with improved patient survival. Moreover, NUMB expression is downregulated in metastatic melanoma cells. NUMB knockdown significantly increased the invasion potential of melanoma cells in a three-dimensional collagen matrix in vitro and in the lungs of a mouse model in vivo; it also significantly upregulated the expression of the NOTCH target gene CCNE. Previous studies suggested that Wnt signaling increases NUMB expression. By mimicking Wnt stimulation through glycogen synthase kinase-3 inhibition, we increased NUMB expression in melanoma cells. Furthermore, a glycogen synthase kinase-3 inhibitor reduced the invasion of melanoma cells in a NUMB-dependent manner. Together, our results suggest that NUMB suppresses invasion and metastasis in melanoma, potentially through its regulation of the NOTCHâCCNE axis and that the inhibitors that upregulate NUMB can exert therapeutic effects in melanoma.
Asunto(s)
Melanoma , Proteínas de la Membrana , Proteínas del Tejido Nervioso , Animales , Línea Celular Tumoral , Glucógeno Sintasa Quinasas/metabolismo , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Vía de Señalización WntRESUMEN
Metastatic melanoma is challenging to clinically address. Although standard-of-care targeted therapy has high response rates in patients with BRAF-mutant melanoma, therapy relapse occurs in most cases. Intrinsically resistant melanoma cells drive therapy resistance and display molecular and biologic properties akin to neural crest-like stem cells (NCLSC) including high invasiveness, plasticity, and self-renewal capacity. The shared transcriptional programs and vulnerabilities between NCLSCs and cancer cells remains poorly understood. Here, we identify a developmental LPAR1-axis critical for NCLSC viability and melanoma cell survival. LPAR1 activity increased during progression and following acquisition of therapeutic resistance. Notably, genetic inhibition of LPAR1 potentiated BRAFi ± MEKi efficacy and ablated melanoma migration and invasion. Our data define LPAR1 as a new therapeutic target in melanoma and highlights the promise of dissecting stem cell-like pathways hijacked by tumor cells. SIGNIFICANCE: This study identifies an LPAR1-axis critical for melanoma invasion and intrinsic/acquired therapy resistance.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Melanoma/patología , Cresta Neural/patología , Células-Madre Neurales/patología , Receptores del Ácido Lisofosfatídico/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Cresta Neural/efectos de los fármacos , Cresta Neural/metabolismo , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Pronóstico , Receptores del Ácido Lisofosfatídico/genética , Transcriptoma , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Melanoma cells share many biological properties with neural crest stem cells. Here we show that the homeodomain transcription factor MSX1, which is significantly correlated with melanoma disease progression, reprograms melanocytes and melanoma cells toward a neural crest precursor-like state. MSX1-reprogrammed normal human melanocytes express the neural crest marker p75 and become multipotent. MSX1 induces a phenotypic switch in melanoma, which is characterized by an oncogenic transition from an E-cadherin-high nonmigratory state toward a ZEB1-high invasive state. ZEB1 up-regulation is responsible for the MSX1-induced migratory phenotype in melanoma cells. Depletion of MSX1 significantly inhibits melanoma metastasis in vivo. These results show that neural crest-like reprogramming achieved by a single factor is a critical process for melanoma progression.
Asunto(s)
Transformación Celular Neoplásica/patología , Reprogramación Celular/fisiología , Factor de Transcripción MSX1/fisiología , Melanocitos/patología , Melanoma/patología , Neoplasias Cutáneas/patología , Animales , Antígenos CD/metabolismo , Cadherinas/metabolismo , Diferenciación Celular/fisiología , Línea Celular Tumoral , Movimiento Celular , Dermis/citología , Dermis/patología , Progresión de la Enfermedad , Células HEK293 , Células Madre Embrionarias Humanas , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/secundario , Factor de Transcripción MSX1/genética , Melanoma/mortalidad , Melanoma/secundario , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteínas del Tejido Nervioso/metabolismo , Cresta Neural/fisiología , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Receptores de Factor de Crecimiento Nervioso/metabolismo , Neoplasias Cutáneas/mortalidad , Ensayos Antitumor por Modelo de Xenoinjerto , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismoRESUMEN
Multipotent stem cells with neural crest-like properties have been identified in the dermis of human skin. These neural crest stem cell (NCSC)-like cells display self-renewal capacity and differentiate into neural crest derivatives, including epidermal pigment-producing melanocytes. NCSC-like cells share many properties with aggressive melanoma cells, such as high migratory capabilities and expression of the neural crest markers. However, little is known about which intrinsic or extrinsic signals determine the proliferation or differentiation of these neural crest-like stem cells. Here we show that, in NCSC-like cells, Notch signaling is highly activated, similar to melanoma cells. Inhibition of Notch signaling reduced the proliferation of NCSC-like cells, induced cell death, and downregulated noncanonical Wnt5a, suggesting that the Notch pathway contributes to the maintenance and motility of these stem cells. In three-dimensional skin reconstructs, canonical Wnt signaling promoted the differentiation of NCSC-like cells into melanocytes. This differentiation was triggered by the endogenous Notch inhibitor Numb, which is upregulated in the stem cells by Wnt7a derived from UV-irradiated keratinocytes. Together, these data reveal a cross talk between the two conserved developmental pathways in postnatal human skin, and highlight the role of the skin microenvironment in specifying the fate of stem cells.