Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

An in vivo avian paradigm to model human melanoma disease and perform fast and relevant preclinical studies

ABSTRACT: Metastatic melanoma patients carrying a BRAFV600 mutation can be treated with BRAF inhibitors (BRAFi), in combination with MEK inhibitors (MEKi), but innate and acquired resistance invariably occurs. Innate resistance can involve transcriptional and epigenetic-based phenotypic adaptations, remaining yet unpredictable. We describe here the development of a highly efficient patient-derived xenograft model adapted to patient melanoma biopsies, using the avian embryo as a host (AVI-PDXTM). In this particular paradigm, we depict a fast and reproducible tumor intake of patient samples within the embryonic skin, preserving key molecular and phenotypical features. We provide the proof of concept that the AVI-PDXTM allows modeling melanoma patient diversity of responses to BRAFi/MEKi, in very short delays, hence positioning it as a valuable tool for the design of personalized medicine assays.

ORGANISM(S): Homo sapiens

PROVIDER: GSE206689 | GEO | 2022/12/19

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Androgen Receptor is a Determinant of Melanoma BRAFi/MEKi Resistance [Clariom_2]

Project description:The majority of BRAFV600 mutant melanomas regress in response to BRAF/MEK inhibitors (BRAFi/MEKi). Yet nearly all relapse within the first two years. Most BRAFi/MEKi-resistant tumors are cross-resistant to immunotherapies, highlighting the need to prevent and circumvent resistance. We recently showed that androgen receptor (AR) activity is required for sustained melanoma cells proliferation and tumorigenesis. Here we find that AR expression is markedly increased in BRAFi resistant melanoma cells as well as in sensitive cells already at very early times of BRAFi exposure. Proliferation and tumorigenicity of BRAFi resistant melanoma cells are blunted by genetic or pharmacologic suppression of AR activity, while AR overexpression is by itself sufficient to rendersmelanoma cells BRAFi/MEKi-resistant. Increased AR elicits transcriptional changes linked with AXL-positive BRAFi resistant subpopulations and induces expression of PAI-1 and EGFR, two determinants of melanoma progression that associate with elevated AR expression in clinical cohorts. Our results point to increased AR signaling as a determinant of melanoma BRAFi resistance, which can be counteracted by AR as well as PAI-1 and EGFR inhibitors.

2023-08-03 | GSE232693 | GEO

Androgen Receptor is a Determinant of Melanoma BRAFi/MEKi Resistance [ChIP-Seq]

2023-08-03 | GSE232690 | GEO

Androgen Receptor is a Determinant of Melanoma BRAFi/MEKi Resistance [Clariom_1]

2023-08-03 | GSE199405 | GEO

BRAF and MEK inhibitor combinations induce potent molecular and immunological effects in NRAS-mutant melanoma cells – insights into mode of action and resistance mechanisms

Project description:About 25% of melanoma harbor activating NRAS mutations, which are associated with aggressive disease therefore requiring a rapid anti-tumor intervention. However, no efficient targeted therapy options are currently available for patients with NRAS-mutant melanoma. MEK inhibitors (MEKi) appear to display a moderate anti-tumor activity and also immunological effects in NRAS-mutant melanoma, providing an ideal backbone for combination treatments. In this study, the MEKi binimetinib, cobimetinib, and trametinib combined with the BRAF inhibitors (BRAFi) encorafenib, vemurafenib, and dabrafenib were investigated for their ability to inhibit proliferation, induce apoptosis and alter the expression of immune modulatory molecules in sensitive NRAS-mutant melanoma cells using 2D and 3D cell culture models and transcriptome analyses. Furthermore, NRAS-mutant melanoma cells resistant to the three BRAFi/MEKi combinations were established to characterize the mechanisms contributing to their resistance. All BRAFi induced a stress response in the sensitive NRAS-mutant melanoma cells thereby significantly enhancing the anti-proliferative and pro-apoptotic activity of the MEKi analyzed. Furthermore, BRAFi/MEKi combinations upregulated immune relevant molecules, such as ICOS-L, components of antigen-presenting machinery and the “don’t eat me signal” molecule CD47 in the melanoma cells. The BRAFi/MEKi-resistant, NRAS-mutant melanoma cells counteracted the molecular and immunological effects of BRAFi/MEKi by upregulating downstream mitogen-activated protein kinase pathway molecules, inhibiting apoptosis and promoting immune escape mechanisms. Together, this study reveals potent molecular and immunological effects of BRAFi/MEKi in sensitive NRAS-mutant melanoma cells that may be exploited in new combinational treatment strategies for patients with NRAS-mutant melanoma.

2023-11-14 | GSE245262 | GEO

Serum IGF1 is a new prognostic marker for resistance to targeted therapies and a predictive marker for anti-IGF1R therapy in melanoma

Project description:In a prospective clinical study, we show that increased serum IGF1 levels in a patient may be a predictive marker of melanoma escape to therapies targeting MAPK pathway (BRAFi/MEKi). In addition, our in vitro and in vivo studies suggest that the response of targeted therapies-resistant melanoma cells to IGF1R inhibitor appears to correlate with the level of IGF1 secretion. Overall, our results suggest that monitoring serum IGF1 levels would individually identify melanoma patients who escape BRAFi/MEKi treatment and may benefit from a combination of targeted therapies and IGF1 signaling inhibition to overcome resistance.

2023-10-30 | GSE239284 | GEO

Ibrutinib blocks YAP1 activation and reverses BRAFi resistance in melanoma cells

Project description:Most BRAF-mutant melanoma tumors respond initially to BRAFi/MEKi therapy, although few patients have durable long-term responses to these agents. The goal of this study was to utilize an unbiased computational approach to identify inhibitors which reverse an experimentally derived BRAFi resistance gene expression signature. Using this approach, we predicted that ibrutinib, a BTK inhibitor, effectively reverses this signature, and we demonstrate experimentally that ibrutinib re-sensitizes a subset of BRAFi-resistant melanoma cells to vemurafenib. Ibrutinib is used clinically as a BTK inhibitor; however, neither BTK deletion nor treatment with acalabrutinib, an analog of ibrutinib with reduced off-target activity, re-sensitized cells to vemurafenib. These data suggest that ibrutinib acts through a BTK-independent mechanism in vemurafenib re-sensitization. To better understand this mechanism, we analyzed the transcriptional profile of ibrutinib-treated BRAFi-resistant melanoma cells and found that the transcriptional profile of ibrutinib was highly similar to that of multiple SRC kinase inhibitors. Since ibrutinib, but not acalabrutinib, has significant off-target activity against multiple SRC family kinases, it suggests that ibrutinib may be acting through this mechanism. Furthermore, genes either upregulated or downregulated by ibrutinib treatment are enriched with YAP1 target genes and we experimentally demonstrate that ibrutinib, but not acalabrutinib, reduces YAP1 activity in BRAFi-resistant melanoma cells. Taken together, these data suggest that ibrutinib, or other SRC family kinase inhibitors, may be useful for treating some BRAFi/MEKi-refractory melanoma tumors.

2020-02-27 | GSE145990 | GEO

Longitudinal monitoring of BRAFV600-mutant melanoma patients on treatment reveals specific macrophage population mediating targeted therapy resistance

Project description:Although treatment of melanoma patients with BRAF and MEK inhibitors has demonstrated impressive clinical outcomes, innate or acquired resistance to targeted therapy remains a major challenge. To uncover resistance mechanisms in patients, we performed single cell RNA sequencing of longitudinal biopsies of the same tumors from four consenting melanoma patients before the start of BRAFi/MEKi treatment and at different time points during treatment. Among the genes most differentially expressed between malignant cells from resistant vs. responding patients was POSTN encoding the secreted factor periostin. POSTN was predicted to predominantly signal to a macrophage population associated with targeted therapy resistance (TTR) in patients and was able to polarize macrophages towards a TTR phenotype. Finally, polarized TTR macrophages protected melanoma cells from MEKi-induced killing, which involved CD44 receptor expression on melanoma cells. Thus, interfering with the protective activity of TTR macrophages might represent a strategy to overcome targeted therapy resistance in melanoma.

2023-12-01 | GSE229908 | GEO

Molecular changes induced in melanoma cells by stromal cells and anti-BRAF therapy.

Project description:Tumor-associated stromal cells can enable cancer cells to become insensitive to therapy. They can promote aggressive phenotype in cancer cells, which become less responsive to drugs such as BRAF inhibitors (BRAFi) used to treat melanomas. To clarify potential mechanism behind stromal influence on melanoma, we analyzed gene expression in Melmet 5 melanoma cells grown as mono-cultures or co-cultures with lung fibroblasts with/without BRAFi. We have shown that Melmet 5 growing as co-cultures gained a de-differentiated, invasive transcriptional state, which is known to be linked to BRAFi-resistance. The transcriptional changes induced by BRAFi were much larger in Melmet 5 mono-cultures compared to co-cultures, indicating a much dampened transcriptional response to BRAFi in melanoma under the influence of fibroblasts. We conclude that interaction with the stromal cells stimulate melanoma cell transition to the invasive de-differentiated phenotype, leading to a worse response to BRAF inhibitors. Total RNA was isolated from Melmet 5 cell line growing as mono- or co-cultures with fibroblasts for 72 hours and treated with BRAFi for the last 24 hours.

2015-08-01 | E-GEOD-67637 | biostudies-arrayexpress

Melanoma therapeutic strategies that select against resistance by exploiting MYC-driven evolutionary convergence

Project description:Diverse pathways can drive resistance to BRAF and MEK inhibitors in BRAF mutant melanoma, suggesting that durable control of resistance will be a major challenge. By combining statistical modeling of genomic data from matched pre-treatment and post-relapse patient tumors with functional interrogation, we discovered that major pathways of resistance converge to activate the transcription factor c-MYC (MYC). MYC expression and pathway gene signatures were suppressed following initial drug treatment, then rebounded during tumor progression independent of the upstream pathway driving resistance. Suppression of MYC activity using either genetic approaches or BET bromodomain inhibition was sufficient to both sensitize diverse BRAFi/MEKi-resistant models and delay resistance in treatment naïve models. Although direct pharmacological inhibition of MYC remains difficult, the BRAFi/MEKi-resistant, MYC-activated state harbors “synthetic lethal” signaling and metabolic dependencies, including those involving SRC family and c-KIT tyrosine kinases as well as glucose, glutamine, and serine metabolic pathways, that can be targeted to create combination therapies that uniquely select against resistance evolution.

2017-11-16 | GSE99923 | GEO

Neratinib, a pan ERBB/HER inhibitor, restores sensitivity of PTEN-null, BRAFV600E melanoma to BRAF/MEK inhibition

Project description:Approximately 50% of melanomas harbor an activating BRAFV600E mutation. Standard of care involves a combination of inhibitors targeting mutant BRAF and MEK1/2, the substrate for BRAF in the MAPK pathway. PTEN loss of function mutations occur in 40% of BRAFV600E melanomas, resulting in increased PI3K/AKT activity that enhances resistance to BRAF/MEK combination inhibitor therapy. To compare the response of PTEN null to PTEN wild type cells in an isogenic background, CRISPR was used to knock out PTEN a melanoma cell line that harbors a BRAFV600E mutation. RNA sequencing and functional kinome analysis revealed the loss of PTEN led to an induction of FOXD3 and an increase in expression of the FOXD3 target gene, ERBB3/HER3. Inhibition of BRAF and MEK1/2 in PTEN null, BRAFV600Ecells dramatically induced expression of ERBB3/HER3 relative to wild type cells. A synergy screen of epigenetic modifiers and kinase inhibitors in combination with BRAFi/MEKi identified the pan ERBB/HER inhibitor, neratinib, as reversing the resistance observed in PTEN null, BRAFV600Ecells. The findings indicate that PTEN null BRAFV600E melanoma exhibits increased reliance on ERBB/HER signaling when treated with clinically approved BRAFi/MEKi combinations. Future studies are warranted to test neratinib reversal of resistance in patient melanomas expressing ERBB3/HER3 in combination with its dimerization partner ERBB2/HER2.

2024-04-23 | GSE255541 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data