Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Mesenchymal tumor cells drive adaptive resistance of Trp53-/- breast tumor cells to inactivated mutant Kras

ABSTRACT: As precision medicine increases the response rate of treatment, tumors frequently bypass inhibition and reoccur. In order for treatment to be effective long term, the mechanisms enabling treatment adaptation need to be understood. Here, we report a mouse model that, in the absence of p53 and the presence of oncogenic KrasG12D, develops breast tumors. Upon inactivation of KrasG12D, tumors initially regress and enter remission. Subsequently, the majority of tumors adapt to the withdrawal of KrasG12D expression and return. KrasG12D-independent tumor cells show a strong mesenchymal profile with active MAPK/ERK signaling. Both KrasG12D-dependent and KrasG12D-independent tumors display a high level of genomic instability, and KrasG12D-independent tumors harbor numerous amplified genes that can activate the MAPK/ERK signaling pathway. Our study identifies both epithelial–mesenchymal transition (EMT) and active MAPK/ERK signaling in tumors that adapt to oncogenic KrasG12D withdrawal in a novel Trp53-/- breast cancer mouse model. To achieve long-lasting responses in the clinic to RAS-fueled cancer, treatment will need to focus in parallel on obstructing tumors from adapting to oncogene inhibition.

ORGANISM(S): Mus musculus

PROVIDER: GSE174441 | GEO | 2022/04/04

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer (part 2)

Project description:Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible KrasG12D-driven mouse model of PDAC has established a critical role for sustained KrasG12D expression in tumor maintenance, providing a model to determine the potential for, and underlying mechanisms of, KrasG12D–independent PDAC recurrence. Here we show that some tumors undergo spontaneous relapse and are devoid of KrasG12D expression and downstream canonical MAPK signaling and instead acquired amplification and overexpression of the transcriptional co-activator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving KrasG12D–independent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidence from human PDAC models, portend a novel mechanism of escape from oncogenic Kras addiction in PDAC.

2014-12-31 | GSE53168 | GEO

Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer (part 1)

2014-12-31 | GSE53167 | GEO

Tovorafenib (DAY101) Monotherapy or in Combination With Other Therapies for Patients With Melanoma and Other Solid Tumors

Project description:This is a Phase 1b/2, multi-center, open label umbrella study of patients ≥12 years of age with recurrent, progressive, or refractory melanoma or other solid tumors with alterations in the key proteins of the RAS/RAF/MEK/ERK pathway, referred to as the MAPK pathway.

| 2385126 | ecrin-mdr-crc

CRAF dimerization with ARAF regulates KRAS driven tumors

Project description:KRAS, mutated in ~30% of all cancers, activates the RAF-MEK-ERK signaling cascade. It has previously been shown that CRAF is required for growth of KRAS mutant lung tumors but the requirement for CRAF kinase activity is unknown. Here, we show that subsets of KRAS mutant tumors are dependent on CRAF for growth. Kinase-dead but not dimer-defective CRAF rescued growth inhibition suggesting that dimerization but not kinase activity is required. Quantitative proteomics demonstrated enrichment of CRAF:ARAF dimers in KRAS mutant cells and depletion of both CRAF and ARAF rescued the CRAF loss phenotype. Mechanistically, CRAF depletion caused sustained ERK activation and induction of cell cycle arrest. Treatment with low dose MEK or ERK inhibitor rescued the CRAF loss phenotype. Our studies highlight the role of CRAF in regulating MAPK signal intensity to promote tumorigenesis downstream of mutant KRAS and suggest that disrupting dimerization or degrading CRAF may have therapeutic benefit.

2021-10-29 | MSV000088285 | MassIVE

Exploiting drug addiction mechanisms to select against MAPKi resistant melanoma

Project description:Melanoma resistant to MAPK inhibitors (MAPKi) displays loss of fitness upon experimental MAPKi withdrawal and, clinically, may be resensitized to MAPKi therapy after a drug holiday. Here, we uncovered and therapeutically exploited the mechanisms of MAPKi addiction in MAPKi-resistant BRAF MUT or NRAS MUT melanoma. MAPKi-addiction phenotypes evident upon drug withdrawal spanned transient cell-cycle slowdown to cell-death responses, the latter of which required a robust phosphorylated ERK (pERK) rebound. Generally, drug withdrawal–induced pERK rebound upregulated p38–FRA1–JUNB–CDKN1A and downregulated proliferation, but only a robust pERK rebound resulted in DNA damage and parthanatos-related cell death. Importantly, pharmacologically impairing DNA damage repair during MAPKi withdrawal augmented MAPKi addiction across the board by converting a cell-cycle deceleration to a caspase-dependent cell-death response or by furthering parthanatos related cell death. Specifically in MEKi-resistant NRAS MUT or atypical BRAF MUT melanoma, treatment with a type I RAF inhibitor intensified pERK rebound elicited by MEKi withdrawal, thereby promoting a cell death–predominant MAPKi-addiction phenotype. Thus, MAPKi discontinuation upon disease progression should be coupled with specific strategies that augment MAPKi addiction.

2017-11-28 | GSE87326 | GEO

Characterization of the genetic mouse model of non-small cells lung cancer p53R172HM-bM-^HM-^Fg/KrasG12D

Project description:Background: Non-small cell lung cancer (NSCLC) accounts for 81% of all cases of lung cancer and they are often fatal because 60% of the patients are diagnosed at an advanced stage. Besides the need for earlier diagnosis, there is a great need for additional effective therapies. In this work we investigated the feasibility of a lung cancer progression mouse model, mimicking features of human aggressive NSCLC cancer, as biological reservoir for potential therapeutic targets and biomarkers. Results:RNA-seq profiling was performed on total RNA extracted from lungs of 30 week-old p53R172HM-bM-^HM-^Fg/KrasG12D and wild type mice to detect fusion genes and gene/exon-level differential expression associated to the increase of tumor mass. Fusion events were not detected in p53R172HM-bM-^HM-^Fg/KrasG12D tumors. Differential expression at exon-level detected 33 genes with differential exon usage. The study provides a complete transcription overview of the p53R172HM-bM-^HM-^Fg/KrasG12D mouse NSCLC model Lung mRNA profiles of 30-week old wild type (WT) and p53R172HM-bM-^HM-^Fg/KrasG12D mice were generated by deep sequencing, in duplicate using Illumina HiSeq2000.

2013-09-25 | E-GEOD-51144 | biostudies-arrayexpress

ECM-enriched mouse lung - TMT-based quantitative mass spectrometry analysis was performed on ECM-enriched preparation from normal murine lung, bleomycin-induced fibrotic lung, primary tumors and lymph node metastasis isolated from the KrasG12D/+p53-/- mouse model of lung adenocarcinoma. Three independent samples were processed and analyzed for each condition. This study identified ECM signatures of normal and diseased lung tissue.

Project description:TMT-based quantitative mass spectrometry analysis was performed on ECM-enriched preparation from normal murine lung, bleomycin-induced fibrotic lung, primary tumors and lymph node metastasis isolated from the KrasG12D/+p53-/- mouse model of lung adenocarcinoma. Three independent samples were processed and analyzed for each condition. This study identified ECM signatures of normal and diseased lung tissue.

2017-06-21 | PXD003517 | Pride

GNPS - Combining HPLC Activity Profiling with Advanced UPLC-HRMS/MS Annotation to Accelerate the Discovery of Bioactive Natural Products

Project description:Dataset containing multiple Hyptis and Artemisia spp. used for the discovery of natural products inhibiting aberrant signaling, namely MAPK/ERK and PI3K/AKT, in melanoma

2021-12-22 | MSV000088606 | GNPS

Generating a RAS expression signature in neuroblastoma

Project description:Mutations affecting the RAS-MAPK pathway frequently occur in relapse neuroblastoma tumors, which suggests that activation of this pathway is associated with a more aggressive phenotype. To explore this hypothesis we generated several model systems to define a neuroblastoma RAS-MAPK pathway signature. We could show that activation of this pathway in primary tumors indeed correlates with poor survival and is associated with known activating mutations in ALK and other RAS-MAPK pathway genes. From integrative analysis we could show that mutations in PHOX2B, CIC and DMD are also associated with an activated RAS-MAPK pathway. Mutation of PHOX2B and deletion of CIC in neuroblastoma cell lines induces activation of the RAS-MAPK pathway. This activation was independent of phosphorylated ERK in the CIC knock out systems. Furthermore, deletion of CIC causes a significant increase in tumor growth in vivo. These results show that the RAS-MAPK pathway is involved in tumor progression, and establish CIC as a powerful tumor suppressor that functions downstream of this pathway in neuroblastoma.

2018-08-22 | GSE115406 | GEO

eIF4F controls ERK MAPK signaling in melanomas with BRAF and NRAS mutations

Project description:The eIF4F translation initiation complex plays a critical role in melanoma resistance to clinical BRAF and MEK inhibitors. In this study, we uncover a novel function of eIF4F in the negative regulation of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway. We demonstrate that eIF4F is essential for maintaining optimal ERK signaling intensity in treatment-naïve melanoma cells harboring BRAF or NRAS mutations. Specifically, the dual-specificity phosphatase DUSP6/MKP3, which acts as a negative feedback regulator of ERK activity, requires continuous production in an eIF4F-dependent manner to limit excessive ERK signaling driven by oncogenic RAF/RAS mutations. Treatment with small molecule eIF4F inhibitors disrupts the negative feedback control of MAPK signaling, leading to ERK hyperactivation and EGR1 overexpression in melanoma cells in vitro and in vivo. Furthermore, our quantitative analyses reveal a high spare signaling capacity in the ERK pathway, suggesting that eIF4F-dependent feedback keeps the majority of ERK molecules inactive under normal conditions. Overall, our findings highlight the crucial role of eIF4F in regulating ERK signaling flux and suggest that pharmacological eIF4F inhibitors can disrupt the negative feedback control of MAPK activity in melanomas with BRAF and NRAS activating mutations.

2024-10-04 | GSE273721 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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