Danny Misiak

Inhibition of RNA-binding proteins enhances immunotherapy in ovarian cancer

Abstract High-grade serous ovarian cancer (HGSC) accounts for more than 70% of ovarian cancer-related deaths, yet therapeutic progress remains stagnant. Among the four molecular subtypes reported for HGSC, the C5 subtype is distinguished by high proliferation and immune evasion with an unfavorable MHC-I/ PD-L1 ratio. However, the molecular drivers of this immune desert state remain largely undefined. Here, we identify RNA-binding proteins (RBPs) as key regulators of immune evasion in C5-HGSC through integrated single-cell and bulk RNA sequencing. We perform a targeted loss-of-function screen in C5-like cell models and find IGF2BP1 as a central mediator of immune evasion in vitro and in vivo. Mechanistically, IGF2BP1 abrogates interferon-gamma signaling by accelerating IRF1 protein degradation, thereby suppressing MHC-I presentation. We also discover that IGF2BP1 decouples PD-L1 expression from IRF1 -dependent transcription and reshapes the immune receptor landscape to limit immune cell infiltration and T cell activation. Therapeutically, the small-molecule BTYNB effectively inhibits IGF2BP1 and synergizes with PD-1 blockade to overcome immune evasion in vivo. Multi-spectral imaging confirms these findings in human HGSC tissues and highlights the role of oncofetal RBPs as molecular drivers of the C5-HGSC subtype. This subtype-wide survey uncovers a previously unrecognized RBP–interferon regulatory axis and establishes RBP inhibition as a therapeutic strategy to enhance immune checkpoint therapy in immunologically cold ovarian tumors.

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.