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Genome-wide CRISPR-Cas9 screen reveals selective vulnerability of ARID1A deficiency Hepatocellular Carcinoma

ABSTRACT: Genome-wide CRISPR-Cas9 screen reveals selective vulnerability of ARID1A deficiency Hepatocellular Carcinoma

PROVIDER: PRJNA948439 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23958309_1.fastq.gz	Fastqsanger.gz
	SRR23958309_2.fastq.gz	Fastqsanger.gz
	SRR23958310_1.fastq.gz	Fastqsanger.gz
	SRR23958310_2.fastq.gz	Fastqsanger.gz
	SRR23958311_1.fastq.gz	Fastqsanger.gz

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Genome-wide CRISPR-Cas9 screen reveals selective vulnerability of ARID1A deficiency Hepatocellular Carcinoma

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Project description:Mutations in ARID1A, encoding a subunit of the BAF chromatin remodeling complex, rank amongst the most common molecular aberrations in human cancer. However, oncogenic consequences of ARID1A mutation in human cells remain poorly defined due to lack of forward human genetic model systems. Here, CRISPR/Cas9 knockout of ARID1A in primary TP53-/- human gastric organoids induced morphologic dysplasia, tumorigenicity and mucinous differentiation but impaired Wnt/b-catenin signaling. Genetic Wnt pathway activation rescued mucinous differentiation, but not hyperproliferation, suggesting alternative essential pathways of ARID1A-mediated transformation. ARID1A loss induced transcriptional regulatory modules characteristic of MSI and EBV subtype human gastric cancer, including FOXM1 regulation of multiple mitotic regulatory genes and BIRC5/survivin. Convergently, high-throughput compound screening indicated selective vulnerability of ARID1A-deficient organoids to BIRC5/survivin inhibition, functionally implicating BIRC5/survivin as an essential mediator of proliferation following initial ARID1A loss. However, CRISPR inactivation of ARID1A in established gastric cancer cell lines did not elicit sensitivity to BIRC5/survivin inhibitors, suggesting that this pathway may be selectively required during the early establishment of tumorigenesis. Overall, we define distinct pathways downstream of oncogenic ARID1A mutation, with non-essential Wnt-inhibited mucinous differentiation in parallel with essential transcriptional FOXM1/BIRC5-stimulated proliferation, indicating the general utility of organoid-based forward genetic cancer analysis in human cells.

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Histone chaperone CAF-1 is a synthetic lethal vulnerability in the context of ARID1A deficiencies [ATAC-Seq]

Project description:Mutations in the BAF chromatin remodeling complex rank among the most frequent genetic alterations in human cancers, many of which result in a loss of function of the respective subunits. Recent genomic and chemical screens have revealed synthetic lethal interactions of BAF complex subunits with each other as well as with further chromatin modifiers. Using an epigenome-focused shRNA library, we identified loss of the histone chaperone complex CAF-1 (chromatin assembly factor 1) as a synthetic lethal vulnerability of ARID1A-deficient cells that is enhanced by the androgen receptor agonist testosterone. In line with antagonistic roles of the CAF-1 and BAF complexes in nucleosome deposition and remodeling, we show that knock-down of CAF-1 subunits results in a partial reversal of the transcriptional and chromatin accessibility effects caused by loss of ARID1A. Together, our findings identify a new functional partner of the BAF chromatin remodeling complex and represent a potential novel strategy for targeting ARID1A-deficient cancers.

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