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A USP28-∆Np63 axis is a druggable vulnerability of squamous tumour formation and maintenance

ABSTRACT: A USP28-∆Np63 axis is a druggable vulnerability of squamous tumour formation and maintenance

PROVIDER: PRJNA533329 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8924531.fastq.gz	Fastqsanger.gz
	SRR8924532.fastq.gz	Fastqsanger.gz
	SRR8924533.fastq.gz	Fastqsanger.gz
	SRR8924534.fastq.gz	Fastqsanger.gz
	SRR8924535.fastq.gz	Fastqsanger.gz

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Similar Datasets

A USP28-∆Np63 axis is a druggable vulnerability of squamous tumour formation and maintenance

Project description:The oncoprotein ∆Np63 is an essential transcriptional master- and cell identity regulator in squamous cell carcinoma (SCC) of various origins, encompassing lung, head and neck, oesophagus, cervix and skin. While in non-transformed cells ∆Np63 protein abundance is tightly regulated by the ubiquitin proteasome system (UPS), in tumours E3-ligases ubiquitylating ∆Np63, such as FBXW7, are commonly mutated or lost, resulting in a hyper-stabilisation of the oncogenic driver. Targeting ∆Np63 protein abundance in SCC could present a possible therapeutic avenue. Here, we report that the deubiquitylase USP28 regulates ∆Np63 protein stability and abundance in SCC by counteracting the degradative UPS system. Interference with USP28 activity by pharmacological inhibition specifically affected human SCC cell lines and, finally, we were able to demonstrate in vivo using CRISPR/Cas9 mouse models that Usp28 is required for SCC induction and maintenance. Hence, targeting USP28 is a viable option to tackle ∆Np63 protein abundance in SCC tumours.

2020-03-04 | GSE129982 | GEO

RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer

Project description:RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer

| PRJNA820858 | ENA

RNA expression in tongue squamous cell carcinoma, tumour free tongue tissue and control tongue

Project description:Tongue squamous cell carcinoma is a tumour type with rather low five year survival, around 60%. The poor survival rate has been ascribed to late detection, a high frequency of locoregional recurrence, the occurrence of secondary primary tumours and death due to comorbidity. One reason for development of recurrence is thought to be the existence of transformed cells in areas adjacent to the primary tumour, cancerization field effect. The aim of this study was to map the changes in the tumour free tongue tissue adjacent to tongue tumours compared with healthy control tongue tissue to better understand the cancerization field effect. Tissue biopsies were collected from tumour (T) and tumour free tissue adjacent to the tumour (TF) from patients with tongue squamous cell carcinoma. Control tissue was collected from latter border of the tongue of tumour free healthy volunteers (C). All samples were homogenized and RNA was extracted. The RNA was biotin labelled and run on Illumina HT-12 bead chip array.

2016-12-21 | E-MTAB-4678 | biostudies-arrayexpress

Galectin-3, a Druggable Vulnerability for KRAS-Addicted Cancers.

Project description:Identifying the molecular basis for cancer cell dependence on oncogenes such as KRAS can provide new opportunities to target these addictions. Here, we identify a novel role for the carbohydrate-binding protein galectin-3 as a lynchpin for KRAS dependence. By directly binding to the cell surface receptor integrin ?v?3, galectin-3 gives rise to KRAS addiction by enabling multiple functions of KRAS in anchorage-independent cells, including formation of macropinosomes that facilitate nutrient uptake and ability to maintain redox balance. Disrupting ?v?3/galectin-3 binding with a clinically active drug prevents their association with mutant KRAS, thereby suppressing macropinocytosis while increasing reactive oxygen species to eradicate ?v?3-expressing KRAS-mutant lung and pancreatic cancer patient-derived xenografts and spontaneous tumors in mice. Our work reveals galectin-3 as a druggable target for KRAS-addicted lung and pancreas cancers, and indicates integrin ?v?3 as a biomarker to identify susceptible tumors.Significance: There is a significant unmet need for therapies targeting KRAS-mutant cancers. Here, we identify integrin ?v?3 as a biomarker to identify mutant KRAS-addicted tumors that are highly sensitive to inhibition of galectin-3, a glycoprotein that binds to integrin ?v?3 to promote KRAS-mediated activation of AKT. Cancer Discov; 7(12); 1464-79. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1355.

| S-EPMC5718959 | biostudies-literature

Expression data from tumour celllines and non-tumour cells.

Project description:Expression data from tumour celllines and non-tumour cells.

| PRJNA523006 | ENA

FBXO7-EYA2 axis in cancer stem cell maintenance

Project description:FBXO7-EYA2 axis in cancer stem cell maintenance

| PRJNA656254 | ENA

Detecting circulating tumour DNA from gestational trophoblastic tumour using common SNPs

Project description:Gestational tumour diagnosis using circulating tumour DNA

| PRJEB49976 | ENA

Druggable targets of squamous cell lung cancer.

Project description:Knowledge of molecular pathogenesis of non-small cell lung cancer has increased remarkably and changed the principles of treatment, especially during the past decade. These advancements have been limited mainly to adenocarcinoma of the lung. Recently, genetic alterations in squamous cell lung cancer (SQCLC) have been detailed and positive results of clinical trials using agents targeting these changes have indicated the potential for improved treatment outcomes for SQCLC.

| S-EPMC3884109 | biostudies-literature

SIRT5 IS A DRUGGABLE METABOLIC VULNERABILITY IN ACUTE MYELOID LEUKEMIA.

Project description:We discovered that the survival and growth of many primary acute myeloid leukemia (AML) samples and cell lines, but not normal CD34+ cells, are dependent on SIRT5, a lysine deacylase implicated in regulating multiple metabolic pathways. Dependence on SIRT5 is genotype-agnostic and extends to RAS- and p53-mutated AML. Results were comparable between SIRT5 knockdown and SIRT5 inhibition using NRD167, a potent and selective SIRT5 inhibitor. Apoptosis induced by SIRT5 disruption is preceded by reductions in oxidative phosphorylation and glutamine utilization, and an increase in mitochondrial superoxide that is attenuated by ectopic superoxide dismutase 2. These data indicate that SIRT5 controls and coordinates several key metabolic pathways in AML and implicate SIRT5 as a vulnerability in AML.

| S-EPMC8133360 | biostudies-literature

Exploiting a metabolic vulnerability in brain tumour stem cells using a brain-penetrant drug with safe profile

Project description:Glioblastoma (GB) remains one of the most treatment refractory and fatal tumour in humans. GB contains a population of self-renewing stem cells, the brain tumour stem cells (BTSC) that are highly resistant to therapy and are at the origin of tumour relapse. Here, we report, for the first time, that mubritinib potently impairs stemness and growth of patient-derived BTSCs harboring different oncogenic mutations. Mechanistically, by employing bioenergetic assays and rescue experiments, we provide compelling evidence that mubritinib acts on complex I of the electron transport chain to impair BTSC stemness pathways, self-renewal and proliferation. Global gene expression profiling revealed that mubritinib alters the proliferative, neural-progenitor-like, and the cell-cycling state signatures. We employed in vivo pharmacokinetic assays to establish that mubritinib crosses the blood-brain barrier. Using preclinical models of patient-derived and syngeneic murine orthotopic xenografts, we demonstrated that mubritinib delays GB tumourigenesis, and expands lifespan of animals. Interestingly, its combination with radiotherapy offers survival advantage to animals. Strikingly, thorough toxicological and behavioral studies revealed that mubritinib does not induce any damage to normal cells and has a well-tolerated and safe profile. Our work warrants further exploration of this drug in in-human clinical trials for better management of GB tumours.

2024-05-15 | GSE253362 | GEO

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