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IGF2BP1 is a targetable SRC/MAPK-dependent driver of invasive growth in ovarian cancer

ABSTRACT: IGF2BP1 is a targetable SRC/MAPK-dependent driver of invasive growth in ovarian cancer

PROVIDER: PRJNA622728 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11470727_1.fastq.gz	Fastqsanger.gz
	SRR11470727_2.fastq.gz	Fastqsanger.gz
	SRR11470728_1.fastq.gz	Fastqsanger.gz
	SRR11470728_2.fastq.gz	Fastqsanger.gz
	SRR11470729_1.fastq.gz	Fastqsanger.gz

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IGF2BP1 is a targetable SRC/MAPK-dependent driver of invasive growth in ovarian cancer

Project description:We identified IGF2BP1 as a marker of the C5 molecular subtype of high-grade ovarian carcinoma (HG-SOC). IGF2BP1 promotes SRC activity and ERK2 expression enhancing the tolerance towards SRC- and MEK-directed inhibitors saracatinib and selumetib. Combination treatment overcomes IGF2BP1-promoted resistance.

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IGF2BP1 is a targetable SRC/MAPK-dependent driver of invasive growth in ovarian cancer.

Project description:Epithelial-to-mesenchymal transition (EMT) is a hallmark of aggressive, mesenchymal-like high-grade serous ovarian carcinoma (HGSOC). The SRC kinase is a key driver of cancer-associated EMT promoting adherens junction (AJ) disassembly by phosphorylation-driven internalization and degradation of AJ proteins. Here, we show that the IGF2 mRNA-binding protein 1 (IGF2BP1) is up-regulated in mesenchymal-like HGSOC and promotes SRC activation by a previously unknown protein-ligand-induced, but RNA-independent mechanism. IGF2BP1-driven invasive growth of ovarian cancer cells essentially relies on the SRC-dependent disassembly of AJs. Concomitantly, IGF2BP1 enhances ERK2 expression in an RNA-binding dependent manner. Together this reveals a post-transcriptional mechanism of interconnected stimulation of SRC/ERK signalling in ovarian cancer cells. The IGF2BP1-SRC/ERK2 axis is targetable by the SRC-inhibitor saracatinib and MEK-inhibitor selumetinib. However, due to IGF2BP1-directed stimulation, only combinatorial treatment effectively overcomes the IGF2BP1-promoted invasive growth in 3D culture conditions as well as intraperitoneal mouse models. In conclusion, we reveal an unexpected role of IGF2BP1 in enhancing SRC/MAPK-driven invasive growth of ovarian cancer cells. This provides a rationale for the therapeutic benefit of combinatorial SRC/MEK inhibition in mesenchymal-like HGSOC.

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