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Gene expression profile analysis of inducible melanotic and amelanotic melanoma in mice

ABSTRACT: We analyzed an inducible melanoma model in TiRP Ink4a/ArfF/F B10.D2 mice based on the conditional deletion in melanocytes of two tumor suppressor genes INK4a/Arf coupled to the expression of the oncogene H-rasG12V and a known tumor antigen (Hujibers et al. Cancer Res. 66:3278,2006; Soudja et al. Cancer Res. 70:3515-3525,2010). About 40% of these mice develop melanomas. Some tumors are heavily pigmented melanotic melanoma and grow slowly (hereafter referred to as “Mela”), but most of the induced tumors are nonpigmented amelanotic melanomas which are more aggressive (hereafter referred to as “Amela”). Gene expression profiles of the two types of tumors and of Amela-derived cell lines established in vitro were analyzed to identify the transcriptional signatures of these two types of tumors (including stromal components and infiltrating cells), as well as that intrinsic to Amela-tumor cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE29304 | GEO | 2013/06/26

SECONDARY ACCESSION(S): PRJNA138637

REPOSITORIES: GEO

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Gene expression profile analysis of inducible melanotic and amelanotic melanoma in mice

Project description:We analyzed an inducible melanoma model in TiRP Ink4a/ArfF/F B10.D2 mice based on the conditional deletion in melanocytes of two tumor suppressor genes INK4a/Arf coupled to the expression of the oncogene H-rasG12V and a known tumor antigen (Hujibers et al. Cancer Res. 66:3278,2006; Soudja et al. Cancer Res. 70:3515-3525,2010). About 40% of these mice develop melanomas. Some tumors are heavily pigmented melanotic melanoma and grow slowly (hereafter referred to as “Mela”), but most of the induced tumors are nonpigmented amelanotic melanomas which are more aggressive (hereafter referred to as “Amela”). Gene expression profiles of the two types of tumors and of Amela-derived cell lines established in vitro were analyzed to identify the transcriptional signatures of these two types of tumors (including stromal components and infiltrating cells), as well as that intrinsic to Amela-tumor cells. 4 Amela and 4 Mela ex-vivo tumors were compared in a dye-swap experiment (8 chips). 4 Amela and 4 Mela ex-vivo tumors were compared to healthy skin (CTRL) (8 chips). 4 Amela ex-vivo tumors and Amela cell lines were compared in a dye-swap experiment (8 chips).

2013-06-26 | E-GEOD-29304 | biostudies-arrayexpress

Comparing gene expression profiles of pigmented and amelanotic (MPNST-like) melanomas arising in the genetically engineered BRAF(V600E)-Cdk4(R24C) mouse melanoma model

Project description:We found that pigmented and amelanotic (MPNST-like) melanomas arise in the genetically engineered BRAF(V600E)-Cdk4(R24C) mouse melanoma model and even in the same animal. To explore the molecular differences between the two type of melanomas in this model we performed global gene expression profiling and pathway analysis to compare the underlying mechanisms. This information was used to identify human melanomas that resemble each type of the mouse melanomas found in the in the genetically engineered BRAF(V600E)-Cdk4(R24C) mouse melanoma model.

2015-12-01 | GSE71879 | GEO

Context-dependent miR-204 and miR-211 affect the biological properties of amelanotic and melanotic melanoma cells [array]

Project description:Despite increasing amounts of experimental evidence depicting the involvement of non-coding RNAs in cancer, the study of BRAFV600E-regulated genes has thus far focused mainly on protein-coding ones. Here, we identify and study the microRNAs that BRAFV600E regulates through the ERK pathway. By performing small RNA sequencing on A375 melanoma cells and a vemurafenib- resistant clone that was taken as negative control, we discover miR-204 and miR-211 as the miRNAs most induced by vemurafenib. We also demonstrate that, although belonging to the same family, these two miRNAs have distinctive features. miR-204 is under the control of STAT3 and its expression is induced in amelanotic melanoma cells, where it acts as an effector of vemurafenib’s anti-motility activity by targeting AP1S2. Conversely, miR-211, a known transcriptional target of MITF, is induced in melanotic melanoma cells, where it targets EDEM1 and consequently impairs the degradation of TYROSINASE (TYR) through the ER-associated degradation (ERAD) pathway. In doing so, miR-211 serves as an effector of vemurafenib’s pro-pigmentation activity. We also show that such an increase in pigmentation in turn represents an adaptive response that needs to be overcome using appropriate inhibitors in order to increase the ef cacy of vemurafenib. In summary, we unveil the distinct and context-dependent activities exerted by miR-204 family members in melanoma cells. Our work challenges the widely accepted “same miRNA family = same function” rule and provides a rationale for a novel treatment strategy for melanotic melanomas that is based on the combination of ERK pathway inhibitors with pigmentation inhibitors.

2017-03-26 | GSE94476 | GEO

Context-dependent miR-204 and miR-211 affect the biological properties of amelanotic and melanotic melanoma cells [miRNA-Seq]

2017-03-26 | GSE94423 | GEO

Proteomic analysis of pigmented and amelanotic melanoma cells

Project description:Mass spectrometry-based proteomics comparison between amelanotic and pigmented melanoma cells for new biomarkers discovery.

2023-02-14 | PXD033192 | Pride

Context-dependent miR-204 and miR-211 affect the biological properties of amelanotic and melanotic melanoma cells

Project description:Context-dependent miR-204 and miR-211 affect the biological properties of amelanotic and melanotic melanoma cells

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Pro-invasion metastasis drivers in early stage melanoma are oncogenes

Project description:Clinical and genomic evidence support the view that the metastatic potential of a primary tumor may be dictated by transforming events acquired early in the tumorigenic process. It has been proposed that the presence of such pro-metastatic events in early-stage tumors reflects their additional capability to function as oncogenes. Here, to test this ‘deterministic’ hypothesis and identify potential pro-metastasis oncogenes, we adopted a comparative oncogenomics-guided functional genetic screening strategy involving (i) global transcriptomic data from two genetically engineered mouse models of melanoma with contrasting metastatic potential, (ii) genomic and transcriptomic profiles of human primary and metastatic melanoma and (iii) an invasion screen in TERT-immortalized human melanocytes and melanoma cells in vitro as well as (iv) evidence of expression selection in human melanoma tissues. This integrated effort led to the identification of 6 genes that are both potently pro-invasive and oncogenic. Further, we show that one such pro-invasion oncogene, ACP5, can confer spontaneous metastasis in vivo, engages a key pathway governing metastasis and is prognostic in human primary melanomas. The tetracycline-inducible MET-driven mouse (iMet) model (Tyr-rtTA;Tet-Met;Ink4a/Arf-/-) was constructed similar to the previously described iHRAS* model (Tyr-rtTA;Tet-HRASV12G;Ink4a/Arf-/-). RNA from cutaneous melanomas derived from iMet (n=6) or iHRAS* (n=6) models were profiled on Affymetrix M430A_2 chips and resultant transcriptomes were compared to generate a phenotype-based (metastatic capable or not) differentially expressed gene list. Cross-species triangulation to human gene expression and copy number aberrations was based on ortholog mapping.

2011-07-11 | E-GEOD-29074 | biostudies-arrayexpress

NRG1/ERBB3 signaling in melanocyte Melan-Ink4a cells

Project description:Neuregulin (NRG) signaling through the receptor tyrosine kinase, ERBB3, is required for embryonic development, and dysregulated signaling has been associated with cancer progression. Here, we show that NRG1/ERBB3 signaling inhibits melanocyte (MC) maturation and promotes undifferentiated, migratory and proliferative cellular characteristics. Embryonic analyses demonstrated that initial MC specification and distribution were not dependent on ERBB3 signaling. However NRG1/ERBB3 signaling was both necessary and sufficient to inhibit differentiation of later stages of MC development in culture. Analysis of tissue arrays of human melanoma samples suggests that ERBB3 signaling may also contribute to metastatic progression of melanoma as ERBB3 was phosphorylated in primary tumors compared with nevi or metastatic lesions. Neuregulin 1-treated MCs demonstrated increased proliferation and invasion and altered morphology concomitant with decreased levels of differentiation genes, increased levels of proliferation genes and altered levels of melanoma progression and metastases genes. ERBB3 activation in primary melanomas suggests that NRG1/ERBB3 signaling may contribute to the progression of melanoma from benign nevi to malignancies. We propose that targeting ERBB3 activation and downstream genes identified in this study may provide novel therapeutic interventions for malignant melanoma. Gene expression changes are compared between Melan-Ink4a cells stimulated with NRG1-b1 (NRG1) for 21 days and NRG1 untreated Melan-INK4a cells in triplicate using Affymetrix Mouse GeneChip 1.0 ST chip .

2010-05-07 | E-GEOD-21463 | biostudies-arrayexpress

Somatic Activation of KIT in Distinct Subtypes of Melanoma

Project description:Melanomas on mucosal membranes, acral skin (soles, palms, and nail bed), and skin with chronic sun-induced damage have infrequent mutations in BRAF and NRAS, genes within the mitogenactivated protein (MAP) kinase pathway commonly mutated in melanomas on intermittently sun-exposed skin. This raises the question of whether other aberrations are occurring in the MAP kinase cascade in the melanoma types with infrequent mutations of BRAF and NRAS. Oncogenic mutations in KIT were found in three of seven tumors with amplifications. Examination of all 102 primary melanomas found mutations and/or copy number increases of KIT in 39% ofmucosal, 36% of acral, and 28% of melanomas on chronically sun-damaged skin, but not in any (0%) melanomas on skin without chronic sun damage. Seventy-nine percent of tumors with mutations and 53% of tumors with multiple copies of KIT demonstrated increased KIT protein levels. KIT is an important oncogene in melanoma. Because the majority of the KIT mutations we found in melanoma also occur in imatinib-responsive cancers of other types, imatinib may offer an immediate therapeutic benefit for a significant proportion of the global melanoma burden. Keywords: melanoma, oncogene, comparative genomic hybridization, KIT

2006-09-09 | GSE4747 | GEO