Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Genome-wide synthetic lethal screen unveils novel CAIX – NFS1/xCT axis as a targetable vulnerability in hypoxic solid tumors.

ABSTRACT: Genome-wide synthetic lethal screen unveils novel CAIX – NFS1/xCT axis as a targetable vulnerability in hypoxic solid tumors.

PROVIDER: PRJNA704708 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Similar Datasets

Genome-wide synthetic lethal screen unveils novel CAIX – NFS1/xCT axis as a targetable vulnerability in hypoxic solid tumors.

Project description:Hypoxia is an important clinicopathological feature of solid tumours that limits response to therapy. Carbonic Anhydrase IX (CAIX) is a hypoxia-induced, pH regulator that has emerged as a viable therapeutic target. Targeting CAIX has demonstrated promise in difficult to treat preclinical models of breast pancreatic, melanoma and brain cancers when combined with chemotherapy and immunotherapy, however resistance ultimately develops and this mechanism is unclear. Here we used an unbiased genome-wide synthetic lethal CRISPR knock-out screen in basal breast cancer cells to identify co-vulnerabilities and mechanisms of compensation for CA9 loss. We identified a redox homeostasis network containing thioredoxin and the iron-sulfur cluster enzyme, cysteine desulfurase, NFS1, indicative of the critical importance of CAIX in this role.

2021-08-28 | GSE167481 | GEO

Pyruvate Anaplerosis is a Targetable Vulnerability in Persistent Leukaemic Stem Cells

Project description:Deregulated oxidative metabolism is a hallmark of leukaemia. While use of tyrosine kinase inhibitors (TKIs) such as imatinib has led to increased survival of chronic myeloid leukaemia (CML) patients, it fails to eradicate disease initiating leukemic stem cells (LSCs). Whether TKI-treated CML LSCs remain metabolically deregulated is unknown. Using clinically and physiologically relevant assays we generated multi-omics datasets that offer unprecedented insight into nutrient fate in patient derived CML LSCs. We demonstrate that LSCs have increased glucose anaplerosis when compared to normal hematopoietic stem cells. While imatinib treatment reverses BCR-ABL-mediated LSC metabolic reprogramming, stable isotope-assisted metabolomics revealed that deregulated glucose anaplerosis is unaffected by imatinib. Encouragingly, genetic ablation of glucose anaplerosis sensitises CML cells to imatinib. Finally, we demonstrate that the clinical oral-available inhibitor MSDC-0160 targets glucose anaplerosis in robust pre-clinical CML models. Collectively these results highlight glucose anaplerosis as a persistent and therapeutically targetable vulnerability in imatinib-treated CML patient samples.

2023-06-27 | GSE216837 | GEO

Single-cell RNA-seq reveals intratumoral heterogeneity in primary uveal melanomas and discloses new targetable vulnerability

Project description:Single-cell RNA-seq reveals intratumoral heterogeneity in primary uveal melanomas and discloses new targetable vulnerability

| PRJNA575854 | ENA

An epigenetic vulnerability in PI3K/AKT inhibition resistant cancers is targetable by both bromodomain and HDAC inhibitors

Project description:An epigenetic vulnerability in PI3K/AKT inhibition resistant cancers is targetable by both bromodomain and HDAC inhibitors

| PRJNA614914 | ENA

MYC dependency in GLS1 and NAMPT is a therapeutic vulnerability in multiple myeloma

Project description:Multiple myeloma is an incurable hematological malignancy evolving from precursor states to advanced phases of the disease. MYC abnormalities play a critical role in the disease progression. Nevertheless, MYC lacks therapeutic drugability, thereby necessitating the exploration of alternative strategies aimed at circumventing the challenges associated with targeting MYC. In this study, we hypothesized that MYC upregulation induces genomic dependencies in tumor cells, creating vulnerabilities that can be exploited therapeutically. We discovered a differential dependency on glutamine metabolism in MYC overexpressing cells. We functionally explored these dependencies as a selective targetable vulnerability in vitro and in vivo. Furthermore, we uncovered a potential synergistic combination that can exacerbated this metabolic vulnerability, Collectively, our in vitro and in vivo results revealed an effective therapeutic combinatory strategy in the context of MYC overexpressing MM.

2024-04-09 | PXD050010 | Pride

mTORC1 promotes malignant large cell/anaplastic histology and is a therapeutically targetable vulnerability in SHH-TP53 mutant medulloblastoma

Project description:mTORC1 promotes malignant large cell/anaplastic histology and is a therapeutically targetable vulnerability in SHH-TP53 mutant medulloblastoma

| PRJNA762305 | ENA

Validation of a non-oncogene encoded vulnerability to Exportin 1 inhibition in pediatric renal tumors

Project description:We identified XPO1 as an aberrantly activated, non-oncogene encoded targetable vulnerability in pediatric renal tumors (Wilms and malignant rhabdoid tumor [MRT]) using OncoTarget, a Master Regular-based precision cancer medicine tool. We demonstrate significant anti-tumor activity of selinexor and eltanexor, two selective XPO1 inhibitors, in patient derived xenograft mice models of Wilms and MRT, and report on a case of successful treatment of a pediatric cancer patient.

2022-03-09 | GSE198000 | GEO

Molecular and functional profiling of chemotolerant cells unveils nucleoside metabolism-dependent vulnerabilities in medulloblastoma

Project description:Chemotherapy resistance is considered one of the main causes of tumor relapse, still challenging researchers for the identification of the molecular mechanisms sustaining its emergence. Here, we setup and characterized chemotherapy-resistant models of Medulloblastoma (MB), one of the most lethal pediatric brain tumors, to uncover targetable vulnerabilities associated to their resistant phenotype. Integration of proteomic, transcriptomic and kinomic data revealed a significant deregulation of several pathways in resistant MB cells, converging to cell metabolism, RNA/protein homeostasis, and immune response, eventually impacting on patient outcome. Moreover, resistant MB cell response to a large library of compounds through a high-throughput screening, highlighted nucleoside metabolism as a relevant vulnerability of chemotolerant cells, with peculiar antimetabolites demonstrating increased efficacy against them and even synergism with conventional chemotherapeutics. Our results suggest that drug-resistant cells significantly rewire multiple cellular processes, allowing their adaptation to a chemotoxic environment, nevertheless exposing alternative actionable susceptibilities for their specific targeting. In this study, we generated and characterized from a proteomic, transcriptional and kinomic point of view chemothrapy-resistant MB cells. Integrated data were then associated to the response of MB resistant cells to a large library of compounds through an high throughput screening approach identifying nucleoside metabolism as a peculiar targetable vulnerability emerged after chemotherapy adaptation.

2023-11-22 | GSE220543 | GEO

MYC dependency in GLS1 and NAMPT is a therapeutic vulnerability in multiple myeloma

Project description:Multiple myeloma is an incurable hematological malignancy evolving from precursor states to advanced phases of the disease. MYC abnormalities play a critical role in the disease progression. Nevertheless, MYC lacks therapeutic drugability, thereby necessitating the exploration of alternative strategies aimed at circumventing the challenges associated with targeting MYC. In this study, we hypothesized that MYC upregulation induces genomic dependencies in tumor cells, creating vulnerabilities that can be exploited therapeutically. We discovered a differential dependency on glutamine metabolism in MYC overexpressing cells. We functionally explored these dependencies as a selective targetable vulnerability in vitro and in vivo. Furthermore, we uncovered a potential synergistic combinations that can exacerbated this metabolic vulnerability, Collectively, our in vitro and in vivo results revealed an effective therapeutic combinatory strategy in the context of MYC overexpressing MM.

2023-09-04 | GSE241948 | GEO

Chromosomal instability adaptation dependencies confer unique targetable vulnerabilities in therapy refractory lethal prostate cancer

Project description:Chromosomal instability (CIN), an ongoing rate of chromosome missegregation during mitosis, is a defining feature of cancer. However, high chromosomal aberrations are detrimental for cell fitness. Here we investigated mechanisms allowing lethal prostate cancer (PCa) to tolerate and survive increasing CIN. Transcriptomic and proteomic analysis of patient datasets and experimental models showed a concomitant increase of CIN and cell division fidelity kinases in lethal PCa. Functional studies identified MASTL as a key kinase to which therapy-resistant PCa cells become addicted to restrain lethal CIN and ensure survival. Combined analysis of transcription factors increased in high CIN PCa patient datasets with detailed promoter analysis identified that MASTL expression is regulated by the Androgen Receptor variant 7 (AR-V7) and E2F7. Finally, targeting MASTL addiction vulnerability in vivo using the small molecule inhibitor GKI-1, improves survival of pre-clinical models. These findings provide proof-of-concept for exploiting CIN levels as a therapeutic approach in cancer.

2023-01-14 | PXD028271 | Pride

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