Project description:As L1CAM expression is associated with metastasis in melanoma patients, it could be a target for the combination therapies. We investigated the functional role of L1CAM in melanoma metastasis by the use of a xenograft model of human melanoma in mice using RNAi mediated L1CAM knockdown melanoma cells.
Project description:Metastasis is the deadliest phase of cancer progression. Experimental models using immunodeficient mice have been used to gain insights into the mechanisms of metastasis. We report here the identification of a âmetastasis aggressiveness gene expression signatureâ derived using human melanoma cells selected based on their metastatic potentials in a xenotransplant metastasis model. Comparison with expression data from human melanoma patients shows that this metastasis gene signature correlates with the aggressiveness of melanoma metastases in human patients. Many genes encoding secreted and membrane proteins are included in the signature, suggesting the importance of tumor-microenvironment interactions during metastasis. Experiment Overall Design: parental cell line vs xenograft model
Project description:Metastasis is the deadliest phase of cancer progression. Experimental models using immunodeficient mice have been used to gain insights into the mechanisms of metastasis. We report here the identification of a âmetastasis aggressiveness gene expression signatureâ derived using human melanoma cells selected based on their metastatic potentials in a xenotransplant metastasis model. Comparison with expression data from human melanoma patients shows that this metastasis gene signature correlates with the aggressiveness of melanoma metastases in human patients. Many genes encoding secreted and membrane proteins are included in the signature, suggesting the importance of tumor-microenvironment interactions during metastasis. Experiment Overall Design: parental cell line vs xenograft model
Project description:Metastasis is the deadliest phase of cancer progression. Experimental models using immunodeficient mice have been used to gain insights into the mechanisms of metastasis. We report here the identification of a âmetastasis aggressiveness gene expression signatureâ derived using human melanoma cells selected based on their metastatic potentials in a xenotransplant metastasis model. Comparison with expression data from human melanoma patients shows that this metastasis gene signature correlates with the aggressiveness of melanoma metastases in human patients. Many genes encoding secreted and membrane proteins are included in the signature, suggesting the importance of tumor-microenvironment interactions during metastasis. Experiment Overall Design: test signature genereated from experiments of parental cell line vs xenograft model
Project description:Knockdown of BHLHE40 expression significantly reduced primary tumor growth and spontaneous lung metastasis in an orthotopic xenograft model of human breast cancer. Gene expression analysis implicated a role of BHLHE40 in hypoxia-induced exosomic secretion of Heparin Binding Epidermal Growth Factor HBEGF, which promotes cell survival and invasion. BHLHE40 induces HBEGF transcription by blocking DNA binding of HDAC1 and HDAC2.
Project description:Melanoma metastasis is a devastating outcome in need of novel preventive therapies. We provide pharmacologic, nolecuar, and genetic evidence establishing the liver-X nuclear hormone receptor (LXR) as a therapeutic target in melanoma. Molecular and genetic experiments revealed these effects to be mediated by LXRb, which elicits these outcomes through transcriptional induction of tumoral and systemic apolipoprotein-E (ApoE). LXRb agonism robustly suppressed tumor growth and metastasis across a wide spectrum of melanoma lines of diverse mutational subtypes established in xenograft, immunocompetent, and genetically-initiated model. We propose a path for the clinical testing of LXRb targeting-a therapeutic approach that uniquely acts by transcriptionally acivating a metastasis suppressor gene. In this experiment we analyzed the effect of GW3965 treatment on gene expression in the MeWo human melanoma cell line. The cells were treated either with DMSO or GW3965 at 1 micromolar for 48 hours, after which the RNA was extracted and gene expression was analyzed by transcriptomic profiling
Project description:Metastatic melanoma is hallmarked by its ability to switch oncogenic MITF expression. Here we tested the impact of STAT3 on melanoma onset and progression in association with MITF expression levels. We established a mouse melanoma model for deleting Stat3 specifically in melanocytes with specific expression of human hyperactive NRASQ61K in an Ink4a deficient background. Mice with tissue specific Stat3 deletion showed an early onset of disease, but displayed significantly diminished lung metastasis. Whole genome expression profiling also revealed a reduced invasion phenotype, which was functionally confirmed in 3D melanoma model systems. Notably, loss or knockdown of STAT3 in mouse or human cells resulted in up-regulation of MITF and induction of cell proliferation. Mechanistically we show that STAT3 induced CEBPa/b expression was sufficient to suppress MITF transcription. Epigenetic analysis by ATAC-seq confirmed that STAT3 enabled CEBPa/b binding to the MITF enhancer region thereby silencing it. We conclude that STAT3 is a metastasis driver able to antagonize the MITF oncogene via direct induction of CEBP family member transcription facilitating RAS-RAF-driven melanoma metastasis.
Project description:The present study demonstrates that ATF-3 plays a tumor suppressing function in melanoma. Overexpression of ATF-3 in metastatic melanoma cell lines significantly inhibited their growth, migration and invasion in vitro as well as inhibited tumor growth in human melanoma xenograft mouse model in vivo.
Project description:Melanoma tumors are highly heterogeneous, comprising of different cell types that vary in their potential for growth and invasion. Heterogeneous expression of the Microphthalmia-associated Transcription Factor (MITF) and the POU domain transcription factor BRN2 (POU3F2) has been found in malignant melanoma. Changing expression of these transcription factors as the disease progresses has been linked to the metastatic mechanism of phenotype switching. We therefore investigated the effects of MITF and BRN2 expression in melanoma growth and metastasis. Depletion of MITF resulted in a cell population that had a slowed cell cycle progression, was less invasive in vitro and had hindered tumor and metastasis forming ability in mouse xenograft studies. BRN2 depletion left a cell population with intact proliferation and invasion in vitro; however metastatic growth was significantly reduced in the mouse xenograft model. These results suggest that the proliferative population within melanoma tumors express MITF, and both MITF and BRN2 are important for metastatic growth in vivo. This finding highlights the importance of BRN2 and MITF expression in development of melanoma metastasis.