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

Author

Bley N, Schott A, Müller S, Misiak D, Lederer M, Fuchs T, Aßmann C, Glaß M, Ihling C, Sinz A, Pazaitis N, Wickenhauser C, Vetter M, Ungurs O, Strauss HG, Thomssen C, and Hüttelmaier S

Subjects
Adherens Junctions genetics, Adherens Junctions metabolism, Animals, Biomarkers, Tumor, Cell Line, Tumor, Disease Models, Animal, Epithelial-Mesenchymal Transition genetics, Female, Humans, Mice, Mitogen-Activated Protein Kinases antagonists & inhibitors, Ovarian Neoplasms drug therapy, Ovarian Neoplasms pathology, Protein Binding, Protein Interaction Domains and Motifs, Protein Kinase Inhibitors pharmacology, RNA-Binding Proteins metabolism, Xenograft Model Antitumor Assays, src Homology Domains, src-Family Kinases antagonists & inhibitors, Gene Expression Regulation, Neoplastic, Mitogen-Activated Protein Kinases metabolism, Ovarian Neoplasms etiology, Ovarian Neoplasms metabolism, RNA-Binding Proteins genetics, Signal Transduction drug effects, src-Family Kinases metabolism
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.

Published
2021
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5. Basilar artery thrombosis during sexual intercourse.

Author

Posa A, Mueller T, Ungurs O, Kornhuber M, and Zierz S

Subjects
Adolescent, Adult, Brain pathology, Female, Humans, Male, Middle Aged, Thrombosis pathology, Basilar Artery pathology, Coitus, Stroke etiology, Thrombosis complications
Abstract

An ischemic stroke during sexual intercourse is very rare. A basilar artery thrombosis during sexual intercourse has not been described previously. We report a young woman with a life-threatening basilar artery thrombosis during sexual intercourse, with a resulting locked-in syndrome. The positive high intensity transient signals (HITS) diagnosis showed a right-to-left shunt and is in line with paradoxic embolism. The molecular genetics revealed a homozygosity 4G/4G in the region PAI1, -675 (promoter polymorphism) as a risk factor for ischemic stroke. Sexual intercourse is a possible, albeit unusual stroke cause, especially in young people., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Published
2020
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