ABSTRACT

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.

摘要

上皮间质转化 (EMT) 是侵袭性间充质样高级别浆液性卵巢癌 (HGSOC) 的标志。SRC 激酶是癌症相关 EMT 的关键驱动因素，通过磷酸化驱动的 AJ 蛋白内化和降解促进粘附连接 (AJ) 分解。在这里，我们显示 IGF2 mRNA 结合蛋白 1 (IGF2BP1) 在间充质样 HGSOC 中上调，并通过以前未知的蛋白质配体诱导但不依赖 RNA 的机制促进 SRC 激活。IGF2BP1 驱动的卵巢癌细胞侵袭性生长基本上依赖于 AJ 的 SRC 依赖性分解。同时，IGF2BP1 以依赖于 RNA 结合的方式增强 ERK2 的表达。这共同揭示了卵巢癌细胞中 SRC/ERK 信号传导的相互刺激的转录后机制。IGF2BP1-SRC/ERK2 轴可被 SRC 抑制剂萨拉卡替尼和 MEK 抑制剂司美替尼靶向。然而，由于 IGF2BP1 定向刺激，只有组合治疗才能有效地克服 3D 培养条件和腹膜内小鼠模型中 IGF2BP1 促进的侵入性生长。总之，我们揭示了 IGF2BP1 在增强 SRC/MAPK 驱动的卵巢癌细胞侵袭性生长中的意外作用。这为间充质样 HGSOC 中组合 SRC/MEK 抑制的治疗益处提供了基本原理。我们揭示了 IGF2BP1 在增强 SRC/MAPK 驱动的卵巢癌细胞侵袭性生长中的意外作用。这为间充质样 HGSOC 中组合 SRC/MEK 抑制的治疗益处提供了基本原理。我们揭示了 IGF2BP1 在增强 SRC/MAPK 驱动的卵巢癌细胞侵袭性生长中的意外作用。这为间充质样 HGSOC 中组合 SRC/MEK 抑制的治疗益处提供了基本原理。