MSX1-Induced Neural Crest-Like Reprogramming Promotes Melanoma Progression

Heppt, Markus V.; Wang, Joshua X.; Hristova, Denitsa M.; Wei, Zhi; Li, Ling; Evans, Brianna; Beqiri, Marilda; Zaman, Samir; Zhang, Jie; Irmler, Martin; Berking, Carola; Besch, Robert; Beckers, Johannes; Rauscher, Frank J.; Sturm, Richard A.; Fisher, David E.; Herlyn, Meenhard; Fukunaga-Kalabis, Mizuho

doi:10.1016/j.jid.2017.05.038

Cited by 29 publications

(41 citation statements)

References 36 publications

(42 reference statements)

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“…Deregulation of FOXD1 expression during tumorigenesis has also been described in non‐small cell lung cancer (NSCLC), prostate cancer and glioma . In the context of melanoma transformation, although the upregulation of TWIST1 and MSX1 is strongly correlated with disease progression, no information is currently available on the role of FOXD1 …”

Section: Discussionmentioning

confidence: 99%

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Loss of neural crest‐associated gene FOXD1 impairs melanoma invasion and migration via RAC1B downregulation

Larribère

Sun

et al. 2018

Intl Journal of Cancer

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Recent studies suggest that malignant melanoma heterogeneity includes subpopulations of cells with features of multipotent neural crest (NC) cells. Zebrafish and mouse models have shown that reactivation of neural crest-specific pathways during transformation determines the invasiveness of melanoma cells. In our study, we show that the neural crest-associated transcription factor FOXD1 plays a key role in the invasion and the migration capacities of metastatic melanomas both in vivo and in vitro. Gene expression profiling analysis identified both an upregulation of FOXD1 in NC and melanoma cells, as well as a downregulation of several genes related to cell invasion in FOXD1 knockdown cells, including MMP9 and RAC1B. Furthermore, we demonstrate that knockdown of RAC1B a tumor-specific isoform of RAC1, significantly impaired melanoma cell migration and invasion and could abrogate enhanced invasiveness induced by FOXD1 overexpression. We conclude that FOXD1 may influence invasion and migration via indirect regulation of MMP9 and RAC1B alternative splicing in melanoma cells.

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Section: Discussionmentioning

confidence: 99%

“…High SLUG expression is seen during early melanomagenesis, however high TWIST1 expression is present in invasive melanoma cells . BRN3A is required for melanoma survival, and forced MSX1 expression in melanocytes leads to a multipotent state and tumor progression …”

Section: Introductionmentioning

confidence: 99%

Loss of neural crest‐associated gene FOXD1 impairs melanoma invasion and migration via RAC1B downregulation

Larribère

Sun

et al. 2018

Intl Journal of Cancer

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“…Additional evidence for a ZEB1 role in melanoma CSC maintenance comes from another study in which the neural crest cell marker Msh homeobox 1 (MSX1) was shown to reprogram differentiated melanocytes to more invasive, NCSC-like melanocytes that can differentiate into other NCSC derivatives, such as neuronal cells. This cell state reprogramming coincides with an increase in ZEB1 and a decrease in ZEB2 and MITF expression [ 112 ]. Moreover, that study has shown that reactivation of notch receptor 1 (NOTCH1) signalling fully reprogrammed differentiated melanocytes into multipotent NCSC-like cells.…”

Section: Zeb1 and Zeb2 In Melanoma Phenotype Switchingmentioning

confidence: 99%

Intrinsic Balance between ZEB Family Members Is Important for Melanocyte Homeostasis and Melanoma Progression

Bruneel

Verstappe

Vandamme

et al. 2020

Cancers

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It has become clear that cellular plasticity is a main driver of cancer therapy resistance. Consequently, there is a need to mechanistically identify the factors driving this process. The transcription factors of the zinc-finger E-box-binding homeobox family, consisting of ZEB1 and ZEB2, are notorious for their roles in epithelial-to-mesenchymal transition (EMT). However, in melanoma, an intrinsic balance between ZEB1 and ZEB2 seems to determine the cellular state by modulating the expression of the master regulator of melanocyte homeostasis, microphthalmia-associated transcription factor (MITF). ZEB2 drives MITF expression and is associated with a differentiated/proliferative melanoma cell state. On the other hand, ZEB1 is correlated with low MITF expression and a more invasive, stem cell-like and therapy-resistant cell state. This intrinsic balance between ZEB1 and ZEB2 could prove to be a promising therapeutic target for melanoma patients. In this review, we will summarise what is known on the functional mechanisms of these transcription factors. Moreover, we will look specifically at their roles during melanocyte-lineage development and homeostasis. Finally, we will overview the current literature on ZEB1 and ZEB2 in the melanoma context and link this to the ‘phenotype-switching’ model of melanoma cellular plasticity.

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“…In other cancers, similar tumor cell-intrinsic mechanisms determine liver metastasis. In melanoma, for example, MSX1induced neural crest-like reprogramming promotes hepatic metastasis (5).…”

Section: Introductionmentioning

confidence: 99%

Hepatic Endothelial Notch Activation Protects against Liver Metastasis by Regulating Endothelial-Tumor Cell Adhesion Independent of Angiocrine Signaling

et al. 2019

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The interaction of tumor cells with organ-specific endothelial cells (EC) is an important step during metastatic progression. Notch signaling in organ-specific niches has been implicated in mediating opposing effects on organotropic metastasis to the lungs and the liver, respectively. In this study, we scrutinized the role of endothelial Notch activation during liver metastasis. To target hepatic EC (HEC), a novel EC subtype-specific Cre driver mouse was generated. Clec4g-Cre tg/wt mice were crossed to Rosa26 N1ICD-IRES-GFP to enhance Notch signaling in HEC (NICD OE-HEC). In NICD OE-HEC mice, hepatic metastasis of malignant melanoma and colorectal carcinoma was significantly reduced. These mice revealed reduced liver growth and impaired metabolic zonation due to suppression of hepatic angiocrine Wnt signaling. Hepatic metastasis, however, was not controlled by angiocrine Wnt signaling, as deficiency of the Wnt cargo receptor Wls in HEC of Wls HEC-KO mice did not affect hepatic metastasis. In contrast, the hepatic microvasculature in NICD OE-HEC mice revealed a special form of sinusoidal capillarization, with effacement of endothelial zonation functionally paralleled by reduced tumor cell adhesion in vivo. Notably, expression of endothelial adhesion molecule ICAM1 by HEC was significantly reduced. Treatment with an anti-ICAM1 antibody significantly inhibited tumor cell adhesion to HEC in wild-type mice confirming that Notch controls hepatic metastasis via modulation of HEC adhesion molecules. As endothelial Notch activation in the lung has been shown to promote lung metastasis, tumor therapy will require approaches that target Notch in an organ-, cell type-, and context-specific manner. Significance: Manipulation of Notch signaling in the endothelium has opposing, organ-specific effects on metastasis to the lung and the liver, demonstrating that this pathway should be targeted in a cell-and context-specific fashion.

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MSX1-Induced Neural Crest-Like Reprogramming Promotes Melanoma Progression

Cited by 29 publications

References 36 publications

Loss of neural crest‐associated gene FOXD1 impairs melanoma invasion and migration via RAC1B downregulation

Loss of neural crest‐associated gene FOXD1 impairs melanoma invasion and migration via RAC1B downregulation

Intrinsic Balance between ZEB Family Members Is Important for Melanocyte Homeostasis and Melanoma Progression

Hepatic Endothelial Notch Activation Protects against Liver Metastasis by Regulating Endothelial-Tumor Cell Adhesion Independent of Angiocrine Signaling

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