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Chromosome 8p-engineering and CRISPR-Cas9 viability screening reveal increased metastatic capacity of liver cancer cells targetable by patient-specific synthetic lethality

ABSTRACT: Chromosome 8p-engineering and CRISPR-Cas9 viability screening reveal increased metastatic capacity of liver cancer cells targetable by patient-specific synthetic lethality

PROVIDER: PRJNA909626 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22561136.fastq.gz	Fastqsanger.gz
	SRR22561137.fastq.gz	Fastqsanger.gz
	SRR22561138.fastq.gz	Fastqsanger.gz
	SRR22561139.fastq.gz	Fastqsanger.gz
	SRR22561140.fastq.gz	Fastqsanger.gz

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Chromosome 8p-engineering and CRISPR-Cas9 viability screening reveal increased metastatic capacity of liver cancer cells targetable by patient-specific synthetic lethality [Th]

Project description:Chromosome 8p-engineering and CRISPR-Cas9 viability screening reveal increased metastatic capacity of liver cancer cells targetable by patient-specific synthetic lethality [Th]

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Chromosome 8p-engineering and CRISPR-Cas9 viability screening reveal increased metastatic capacity of liver cancer cells targetable by patient-specific synthetic lethality [Cas9]

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Chromosome 8p-engineering and CRISPR-Cas9 viability screening reveal increased metastatic capacity of liver cancer cells targetable by patient-specific synthetic lethality [Th]

Project description:Large-scale chromosomal aberrations are prevalent in human cancer but their functional effects remain poorly understood. We describe the establishment of chromosome-engineered hepatocellular carcinoma cell lines using a dual guided CRISPR-Cas9 genome editing strategy. A mega base-sized region on chromosome 8p (chr8p) was heterozygously deleted mimicking a frequently observed copy number alteration (CNA) of solid tumors. Using this unique model system, we delineated the functional consequences of chr8p loss and its impact on metastatic behavior and patient survival. We found that metastasis associated genes on chr8p act in concert to induce an aggressive and invasive phenotype characteristic for chr8p deleted tumors. The conjunction of engineered chromosome-scale CNAs and genome-wide CRISPR-Cas9 viability screenings served as a powerful tool for the discovery of novel synthetic lethal targets and vulnerabilities accompanying patient-specific copy number changes. Using this target identification strategy, we showed that chr8p deletion sensitizes tumor cells to targeting of the reactive oxygen sanitizing enzyme Nudix hydrolase 17 (NUDT17).

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Chromosome 8p-engineering and CRISPR-Cas9 viability screening reveal increased metastatic capacity of liver cancer cells targetable by patient-specific synthetic lethality [Cas9]

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Chromosome 8p-engineering and CRISPR-Cas9 viability screening reveal increased metastatic capacity of liver cancer cells targetable by patient-specific synthetic lethality

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-12-27 | GSE220320 | GEO

Chromosome 8p engineering reveals increased metastatic potential targetable by patient-specific synthetic lethality in liver cancer.

Project description:Large-scale chromosomal aberrations are prevalent in human cancer, but their function remains poorly understood. We established chromosome-engineered hepatocellular carcinoma cell lines using CRISPR-Cas9 genome editing. A 33-mega-base pair region on chromosome 8p (chr8p) was heterozygously deleted, mimicking a frequently observed chromosomal deletion. Using this isogenic model system, we delineated the functional consequences of chr8p loss and its impact on metastatic behavior and patient survival. We found that metastasis-associated genes on chr8p act in concert to induce an aggressive and invasive phenotype characteristic for chr8p-deleted tumors. Genome-wide CRISPR-Cas9 viability screening in isogenic chr8p-deleted cells served as a powerful tool to find previously unidentified synthetic lethal targets and vulnerabilities accompanying patient-specific chromosomal alterations. Using this target identification strategy, we showed that chr8p deletion sensitizes tumor cells to targeting of the reactive oxygen sanitizing enzyme Nudix hydrolase 17. Thus, chromosomal engineering allowed for the identification of novel synthetic lethalities specific to chr8p loss of heterozygosity.

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8p Loss of Heterozygosity triggers metastasis and drug resistance

Project description:Chromosome arm deletions are frequently observed in human cancers. Such large-scale aberrations may trigger phenotypes distinct from those that arise by loss of single genes. Using TALEN-based genomic engineering, we generated cell models with targeted 8p loss-of-heterozygosity (LOH) that mimics an 8p deletion commonly found in breast cancer patients. 8p LOH triggered up-regulation of the mevalonate pathway. The alterations in lipid metabolism led to increased metastatic potential and drug resistance of 8p-deleted cells that are in agreement with poorer survival rates of breast cancer patients harbouting 8p LOH. Our findings also suggest novel therapeutic strategies for treatment of 8p LOH tumors.

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Project description:This project aimed to identify a specific target for chromosome 8p deletions. Using large-scale functional-genomic screening data of over 527 well-characterized cancer cell lines. We were able to identify the dependency of SLC25A28 (Mitoferrin-2, MFRN2), a mitochondrial iron transporter, in chromosome 8p deleted cancer cell lines. Interestingly, we found that SLC25A37 (Mitoferrin-1, MFRN1), the paralog of MFRN2, resides on chromosome 8p and is frequently deleted in liver cancer. We found a strong correlation between the cellular dependency on MFRN2 and the MFRN1 expression levels, possibly explaining why MFRN2 is a synthetic lethal target for 8p deletions. Our study discovered MFRN2 as a target for a therapeutic strategy in chromosome 8p deleted cancer specimens. Further, it revealed MFRN1 as a biomarker that predicts the response to MFRN2-directed therapy.

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Chromosome engineering to correct a complex rearrangement on Chromosome 8 reveals the effects of 8p syndrome on gene expression and neural differentiation

Project description:Chromosomal rearrangements on the short arm of chromosome 8 cause 8p syndrome, a rare developmentaldisorder characterized by neurodevelopmental delays, epilepsy, and cardiacabnormalities.While significantprogress has been made in managing the symptoms of 8p syndrome and otherconditionscaused by large-scalechromosomalaneuploidies, no therapeutic approach has yet been demonstrated to target the underlyingdisease-causingchromosome.Here, we establish a two-step approachto eliminate theabnormalcopy ofchromosome 8and restore euploidy in cells derived from an individual with a complex rearrangement ofchromosome 8p.Transcriptomic analysis revealed 361 differentially expressed genes between the proband andthe euploid revertant, highlighting genes both within and outside the 8p region that may contribute to 8psyndrome pathology. Our work demonstrates the feasibilityof using chromosome engineering to correct complexaneuploidies invitro and suggests a potential therapeutic avenue for disorders caused by chromosomalrearrangements.

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