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MITF and BRN2 contribute to metastatic growth after dissemination of melanoma.

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE101434 | GEO | 2017/08/16

SECONDARY ACCESSION(S): PRJNA394227

REPOSITORIES: GEO

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BRN2 expression increases anoikis resistance in melanoma.

Project description:Melanoma tumors are highly heterogeneous, comprising of many cell populations that vary in their potential for growth and invasion. Differential transcription factor expression contributes to these phenotypic traits. BRN2, a member of the POU domain family of transcription factors is thought to play important roles in melanoma invasion and metastasis. However, how BRN2 functions during the metastatic process of melanoma remains largely unknown. We therefore investigated the effects of BRN2 expression in melanoma cells with no or low constitutive expression using a doxycycline-inducible system. Induction of BRN2 expression led to reduced proliferation and partial resistance to an inhibitor of mutated BRAF. Whole genome profiling analysis revealed novel targets and signaling pathway changes related to prevention of cell death induced by detachment from the extracellular matrix, known as anoikis resistance. Further investigation confirmed increased survival of BRN2 expressing cell lines in non-adherent conditions. Functionally, expression of BRN2 promoted induction of c-MET levels as well as increased phosphorylation of STAT3. Treatment with crizotinib, a c-MET inhibitor, decreased cellular viability of BRN2 expressing cells under non-adherent conditions to death by anoikis. These results highlight the importance of a largely overlooked transcription factor in the progression and metastasis of melanoma, and may suggest a strategy to target BRN2 expressing cells resistant to therapy and cell death by anoikis.

2020-02-25 | GSE145806 | GEO

Homo sapiens

Project description:MITF and BRN2 contribute to metastatic growth after dissemination of melanoma.

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Interactions of melanoma cells with distal keratinocytes trigger metastasis via Notch signaling inhibition of MITF

Project description:The most critical stage in initiation of melanoma metastasis is the radial to vertical growth transition, yet the triggers of this transition remain elusive. We introduce a novel perspective, suggesting that the microenvironment drives melanoma metastasis independently of mutation acquisition. Here we examined the changes in microenvironment that occur during melanoma radial growth. We show that direct contact of melanoma cells with the remote epidermal layer triggers vertical invasion via Notch signaling activation, the latter serving to inhibit MITF function. Briefly, within the native Notch ligand-free microenvironment, MITF, the melanocyte lineage master regulator, binds and represses miR-222/221 promoter in an RBPJK-dependent manner. However, when radial growth brings melanoma cells into contact with distal differentiated keratinocytes that express Notch ligands, the activated Notch intracellular domain impairs MITF binding to miR-222/221 promoter. This de-repression of miR-222/221 expression triggers initiation of invasion. Our findings may direct novel prevention opportunities via targeting specific microenvironment. Two replicates of Notch-activated cells that were seeded on Delta-like-1 (DLL1) (2 ng/µl ) coated plates were compared to two replicates of cells without Notch activation. The goal of this experiment is to evaluate the changes of miRs expression in melanoma cells upon Notch signaling activation.

2015-07-30 | E-GEOD-69403 | biostudies-arrayexpress

STAT3 promotes melanoma metastasis by CEBP-induced repression of the MITF pigmentation pathway

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.

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Interactions of melanoma cells with distal keratinocytes trigger metastasis via Notch signaling inhibition of MITF

2015-07-30 | GSE69403 | GEO

Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through a NGFR-dependent mechanism

Project description:Secreted extracellular vesicles are known to influence the tumor microenvironment and promote metastasis. In this work, we have analyzed the involvement of extracellular vesicles in the establishment of lymph node pre-metastatic niches by melanoma cells. We found that small extracellular vesicles (sEVs) derived from highly metastatic melanoma cell lines spread broadly through the lymphatic system and were taken up by lymphatic endothelial cells, reinforcing lymph node metastasis. Melanoma-derived sEVs induce lymphangiogenesis, a hallmark of pre-metastatic niche formation, in vitro and in lymphoreporter mice in vivo. We found that neural growth factor receptor (NGFR) is secreted in melanoma-derived small extracellular vesicles and shuttled to lymphatic endothelial cells, inducing lymphangiogenesis and tumor cell adhesion through the activation of ERK and NF-B pathways and ICAM1 expression. Importantly, ablation or inhibition of NGFR in sEVs reversed the lymphangiogenic phenotype, decreased melanoma lymph node metastasis and extended the survival. Importantly, analysis of NGFR expression in lymph node metastases and matched primary tumors shows that levels of MITF+NGFR+ lymph node metastatic cells are correlated with disease outcome. Our data support the idea that NGFR secreted in sEVs favors lymph node pre-metastatic niche formation and lymph node metastasis in melanoma

2021-08-05 | PXD024852 | Pride

Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis by a NGFR-dependent mechanism

Project description:Secreted extracellular vesicles are known to influence the tumor microenvironment and promote metastasis. In this work, we have analyzed the involvement of extracellular vesicles in establishing the lymph node pre-metastatic niche by melanoma cells. We found that small extracellular vesicles (sEVs) derived from highly metastatic melanoma cell lines spread broadly through the lymphatic system and are taken up by lymphatic endothelial cells reinforcing lymph node metastasis. Melanoma-derived sEVs induce lymphangiogenesis, a hallmark of pre-metastatic niche formation, in vitro and in lymphoreporter mice in vivo. Analysis of involved factors demonstrated that the neural growth factor receptor (NGFR) is secreted in melanoma-derived small extracellular vesicles and shuttled to lymphatic endothelial cells inducing lymphangiogenesis and tumor cell adhesion through the activation of ERK and NF-B pathways and ICAM1 expression. Importantly, ablation or inhibition of NGFR in sEVs reversed the lymphangiogenic phenotype, decreased melanoma lymph node metastasis and extended mice survival. Importantly, analysis of NGFR expression in lymph node metastases and matched primary tumors shows that levels of MITF+NGFR+ lymph node metastatic cells are correlated with disease outcome. Our data support that NGFR is secreted in sEVs favoring lymph node pre-metastatic niche formation and lymph node metastasis in melanoma.

2021-07-16 | PXD024108 | Pride

RNA-seq of ATF-3 overexpressing and Neomycin control melanoma cell lines

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.

2020-09-15 | GSE152460 | GEO

siRNA-mediated knockdown of MITF and PAX3 in metastatic melanoma cell lines

Project description:The transcription factors PAX3 and MITF are required for the development of the neural crest and melanocyte lineage, and both proteins play important roles in melanoma cell growth and survival. PAX3 transcriptionally activates MITF expression during neural crest development, but the relationship between these transcription factors during melanocyte development and in melanoma cells is currently poorly understood. This study aimed to further our understanding of the interaction between transcriptional networks controlled by PAX3 and MITF by assessing the effect of siRNA-mediated knockdown of PAX3 and MITF in metastatic melanoma cell lines. The goals of this study were to determine (i) if PAX3 is required for maintaining expression of MITF in melanoma and melanocyte cell lines; (ii) whether PAX3 and MITF independently, or redundantly, influence growth and survival in melanoma cell lines; and (iii) to investigate the respective roles of PAX3 and MITF expression in melanoma cell differentiation. Microarrays were used to measure global changes in transcript expression in response to siRNA-mediated knockdown of PAX3 or MITF compared to non-targeting controls in two metastatic melanoma cells lines. RNA was isolated from two different metastatic melanoma cell lines 30 hours after one of four different treaments: (i) transfection with siRNA targeting PAX3; or (ii) transfection with siRNA targeting MITF; or (iii) or transfection with siRNA targeting luciferase (non-targeting negative control); or (iv) treatment with media only (control). Therefore, eight samples were used for gene expression profiling by using GeneChip arrays, with one replicate per cell line per treatment.

2010-01-01 | E-GEOD-16249 | biostudies-arrayexpress

Affymetrix copy number data for melanoma cell line mapping

Project description:We searched for putative phenotypic and genotypic differences between primary lesions and melanoma metastasis. Therefore, we investigated melanoma cells derived either from the primary tumor or from lymph node metastasis of the same individual patient. In vitro studies revealed high migratory and anchorage-independent growth of metastasis-derived cells. Unexpectedly, whole genome DNA analysis displayed a total of 10 homozygous losses in the primum-derived cell line, whereas the metastasis–derived cell line only shared 5 of those losses. We further tested these cells in a mouse model for intradermal melanoma growth and detected fast growth of the metastasis-derived cell line and delayed growth of primum-derived cells. However, after re-grafting of primum-derived cells, tumor growth kinetic was accelerated and therefore comparable to metastasis-derived cells. Moreover, re-grafted primum-derived cells now also harboured the same reduced DNA deletion pattern, identical to human metastasis-derived cells. We conclude that our xenotransplantation model mimics clonal selection from a heterogeneous starting population, and we suggest that tumor cell progression at the metastatic niche can occur parallel and independently from the primary tumor. Therefore, we propose that for mutation-targeted therapy approaches, the genotyping procedure should include primary as well as metastatic melanoma biopsies. DNA was extracted from in vitro grown cell lines, and Affymetrix SNP6.0 arrays were performed according to the manufacturer's instructions. Intensity Log2 ratios were used to manually search for homozygous deletions via the genotyping console.

2011-04-07 | E-GEOD-22461 | biostudies-arrayexpress

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