Development and characterization of a clinically relevant mouse model of melanoma brain metastasis

Morsi, Amr; Gaziel-Sovran, Avital; Cruz‐Muñoz, William; Kerbel, Robert S.; Golfinos, John G.; Hernando, Eva; Wadghiri, Youssef Zaim

doi:10.1111/pcmr.12114

Cited by 20 publications

(12 citation statements)

References 16 publications

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“…Next we examined whether FUT8 is required for the maintenance or growth of existing metastasis using a model based on intracardiac instillation of tumor cells (Morsi et al, 2013). We generated 4L melanoma cells stably transduced with lentiviral particles carrying either a doxycycline (DOX)-inducible shRNA targeting FUT8 (pTRIPZ/FUT8 shC) or a scrambled control (pTRIPZ/shSCR) and a luciferase reporter vector constitutively expressing green fluorescent protein (GFP).…”

Section: Resultsmentioning

confidence: 99%

“…Fluorescent intensity of macrometastases was quantified by Image J software. Intracardiac inducible metastasis model: To check the effect of FUT8 modulation of existing metastasis we used a model based on intracardiac instillation of tumor cells (Morsi et al, 2013). 4L cells were first transduced with GFP/luciferase reporter lentivirus and then with DOX inducible shSCR or FUT8 shC lentiviruses.…”

Section: Star*methodsmentioning

confidence: 99%

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A Systems Biology Approach Identifies FUT8 as a Driver of Melanoma Metastasis

et al. 2017

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SUMMARY Association of aberrant glycosylation with melanoma progression is based mainly on analyses of cell lines. Here we present a systems-based study of glycomic changes and corresponding enzymes associated with melanoma metastasis in patient samples. Upregulation of core fucosylation (FUT8) and downregulation of α-1,2 fucosylation (FUT1, FUT2) were identified as features of metastatic melanoma. Using both in vitro and in vivo studies, we demonstrate FUT8 is a driver of melanoma metastasis which, when silenced, suppresses invasion and tumor dissemination. Glycoprotein targets of FUT8 were enriched in cell migration proteins including the adhesion molecule L1CAM. Core fucosylation impacted L1CAM cleavage and the ability of L1CAM to support melanoma invasion. FUT8 and its targets represent therapeutic targets in melanoma metastasis.

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Section: Resultsmentioning

confidence: 99%

Section: Star*methodsmentioning

confidence: 99%

A Systems Biology Approach Identifies FUT8 as a Driver of Melanoma Metastasis

et al. 2017

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“…This is a useful technique to determine the proclivity of a specific cell line to favor particular sites of metastasis. Brain metastases in this experiment were produced in approximately one quarter of the mice and with rapid onset [ 115 ]. However, as with left ventricle injections in immunodeficient mice, early steps in metastasis are bypassed.…”

Section: Animal Models Of Melanoma Brain Metastasismentioning

confidence: 99%

Melanoma Brain Metastasis: Mechanisms, Models, and Medicine

Kircher

Silvis

Cho

et al. 2016

IJMS

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The development of brain metastases in patients with advanced stage melanoma is common, but the molecular mechanisms responsible for their development are poorly understood. Melanoma brain metastases cause significant morbidity and mortality and confer a poor prognosis; traditional therapies including whole brain radiation, stereotactic radiotherapy, or chemotherapy yield only modest increases in overall survival (OS) for these patients. While recently approved therapies have significantly improved OS in melanoma patients, only a small number of studies have investigated their efficacy in patients with brain metastases. Preliminary data suggest that some responses have been observed in intracranial lesions, which has sparked new clinical trials designed to evaluate the efficacy in melanoma patients with brain metastases. Simultaneously, recent advances in our understanding of the mechanisms of melanoma cell dissemination to the brain have revealed novel and potentially therapeutic targets. In this review, we provide an overview of newly discovered mechanisms of melanoma spread to the brain, discuss preclinical models that are being used to further our understanding of this deadly disease and provide an update of the current clinical trials for melanoma patients with brain metastases.

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“…These cells were effectively visualized by magnetic resonance imaging (MRI) followed by automated analysis. Our group combined ultrasound-guided intra-cardiac injection of melanoma cells as a minimally invasive, high-throughput method of induction, with MRI-assisted tumor segmentation, 3D reconstruction and quantitative volumetric analysis, to precisely map and measure parenchymal B-Mets (Morsi et al, 2013). This approach takes advantage of the paramagnetic nature of melanin, which renders a signal brightening endogenous effect in tracer-free T1-weighted MRI (Isiklar et al, 1995).…”

Section: In Vivo Models Of Melanoma Brain Metastasismentioning

confidence: 99%

In vivo Modeling and Molecular Characterization: A Path Toward Targeted Therapy of Melanoma Brain Metastasis

Gaziel-Sovran¹,

Osman²,

Hernando³

2013

Front. Oncol.

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Brain metastasis (B-Met) from melanoma remains mostly incurable and the main cause of death from the disease. Early stage clinical trials and case studies show some promise for targeted therapies in the treatment of melanoma B-Met. However, the progression-free survival for currently available therapies, although significantly improved, is still very short. The development of new potent agents to eradicate melanoma B-Met relies on the elucidation of the molecular mechanisms that allow melanoma cells to reach and colonize the brain. The discovery of such mechanisms depends heavily on pre-clinical models that enable the testing of candidate factors and therapeutic agents in vivo. In this review we summarize the effects of available targeted therapies on melanoma B-Met in the clinic. We provide an overview of existing pre-clinical models to study the disease and discuss specific molecules and mechanisms reported to modulate different aspects of melanoma B-Met and finally, by integrating both clinical and basic data, we summarize both opportunities and challenges currently presented to researchers in the field.

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Development and characterization of a clinically relevant mouse model of melanoma brain metastasis

Cited by 20 publications

References 16 publications

A Systems Biology Approach Identifies FUT8 as a Driver of Melanoma Metastasis

A Systems Biology Approach Identifies FUT8 as a Driver of Melanoma Metastasis

Melanoma Brain Metastasis: Mechanisms, Models, and Medicine

In vivo Modeling and Molecular Characterization: A Path Toward Targeted Therapy of Melanoma Brain Metastasis

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