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

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.

上皮间质转化（Epithelial-to-mesenchymal transition, EMT）是侵袭性间质样高级别浆液性卵巢癌（high-grade serous ovarian carcinoma, HGSOC）的标志性病理特征。SRC激酶是癌症相关EMT的关键驱动因子，可通过磷酸化驱动黏着连接（adherens junction, AJ）蛋白的内吞与降解，促进黏着连接解离。本研究发现，胰岛素样生长因子2 mRNA结合蛋白1（IGF2 mRNA-binding protein 1, IGF2BP1）在间质样HGSOC中表达上调，并通过一种此前未知的蛋白质-配体诱导、但不依赖RNA的机制激活SRC激酶。卵巢癌细胞中IGF2BP1介导的侵袭性生长，本质上依赖于SRC激酶介导的黏着连接解离过程。与此同时，IGF2BP1以依赖RNA结合的方式上调细胞外调节蛋白激酶2（ERK2）的表达。综上，本研究揭示了卵巢癌细胞中SRC/ERK信号通路协同激活的转录后调控机制。IGF2BP1-SRC/ERK2轴可被SRC抑制剂萨拉卡替尼（saracatinib）和MEK抑制剂司美替尼（selumetinib）靶向干预。然而，由于IGF2BP1的驱动作用，仅联合用药可有效抑制IGF2BP1促进的侵袭性生长，该效应在三维培养体系及小鼠腹腔模型中均得到验证。本研究最终揭示了IGF2BP1在增强SRC/丝裂原活化蛋白激酶（mitogen-activated protein kinase, MAPK）介导的卵巢癌细胞侵袭性生长中的意外作用，为间质样HGSOC采用SRC/MEK联合抑制疗法提供了理论依据。