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

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 mesenchymallike HGSOC.

The role of Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) as m6A readers in cancer

“…Nonetheless, all three IGF2BPs are highly expressed and function as independent prognostic factors in a variety of cancers, including lung cancer 89 , 90 , liver cancer 91 - 93 , breast cancer 94 , 95 , colorectal cancer 96 - 98 , pancreatic cancer 99 - 101 , prostate cancer 102 , bladder cancer 103 - 105 , thyroid cancer 106 - 108 , gastric cancer 109 , 110 , renal cell carcinoma 111 , ovarian cancer 112 , 113 , esophageal squamous cell carcinoma 114 , 115 , acute myeloid leukemia 116 . In addition to the high expression of the IGF2BPs itself, intercellular communication factors, such as tumor-secreted extracellular vesicles (EVs), can maintain the stability of IGF2BPs in cells to promote the development of cancer.…”

IGF2BP1, a Conserved Regulator of RNA Turnover in Cancer

“…RNA-sequencing, qRT-PCR or Western blotting was performed 96 h (PANC-1) or 72 h (all other cell lines) post transfection referring to approximately three doublings. For RNA decay analyses, cells were treated with Actinomycin D (5 μM, Sigma Aldrich) for indicated time points 72 h upon transfection.mRNA levels were quantified by QRT-PCR based on the SYBRGreenI ® technology as previously described (Bley et al, 2020). Western blotting using the LI-COR Odyssey infrared scanning system for detection was performed as previously described in detail (Bley et al, 2020).…”

A Risk Score Model Incorporating Three m6A RNA Methylation Regulators and a Related Network of miRNAs-m6A Regulators-m6A Target Genes to Predict the Prognosis of Patients With Ovarian Cancer

“…For example, Gu et al (2004) showed that increased IGF2BP1 expression is associated with an advanced clinical stage and poor prognosis in patients with OC. As shown in the study by Bley et al (2021) , IGF2BP1 is a targetable SRC/MAPK-dependent driver of invasive growth in OC. In addition, Qin et al (2017) reported that the restoration of miR-708 sensitizes OC cells to cisplatin via the IGF2BP1/Akt pathway.…”