IGF2BP1 is a targetable SRC/MAPK-dependent driver of invasive growth in ovarian cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE147980 | GEO | 2020/08/24
REPOSITORIES: GEO
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Project description:The Hippo/YAP1 signaling pathway regulates normal development by controlling contact inhibition of growth. In cancer, YAP1 activation is often dysregulated, leading to excessive tumor growth and metastasis. We demonstrate that the RNA-binding protein IGF2BP1 impedes the repression of YAP1 by Hippo signaling in carcinomas. IGF2BP1 stabilizes YAP1 mRNA and enhances YAP1 protein synthesis through an m6A-dependent interaction with the 3’UTR of the YAP1 mRNA. This results in increased nuclear YAP1 accumulation in IGF2BP1-expressing ovarian cancer, boosting transcriptional activity and bypassing contact inhibition. Inhibiting IGF2BP1-mRNA binding using the small molecule BTYNB reduces YAP1 levels and transcriptional activity, leading to significant growth inhibition in carcinoma cells and ovarian cancer organoids. Conversely, SRC inhibition via Saracatinib only impacts epithelial-like tumor cells, suggesting that the impact of SRC is limited by the stalling of YAP1 at adherens junction. This is particularly significant in de-differentiated, rather mesenchymal carcinoma-derived cells, which exhibit high IGF2BP1 and YAP1 expression, rendering them less reliant on SRC -directed growth stimulation. In such invasive carcinoma models, the combined inhibition of SRC and IGF2BP1 or YAP1/TAZ by Verteporfin proved superior over monotherapies. These findings highlight the therapeutic potential of targeting IGF2BP1, a key regulator of oncogenic transcription networks.
2024-12-09 | GSE283587 | GEO
Project description:IGF2BP1 is a targetable SRC/MAPK-dependent driver of invasive growth in ovarian cancer
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Project description:In this project we aim to identify phosphorylation sites of IGF2BP1 that have not been discovered yet in mass spec experiments due to insufficient coverage. To this end we used Pro-Alanase treatment that produced detectable peptides in regions that are not covered by commonly used approaches. IGF2BP1 phosphorylation was investigated in vitro by treating purified IGF2BP1 with Src and in vivo by comparing immunoprecipitated IGF2BP1 from unstressed and stressed (1.5 h thapsigargin or 2 h or arsenite) HEK293T cells expressing GFP-labeled IGF2BP1.
2024-11-13 | PXD056497 | Pride
Project description:High-grade serous ovarian cancer (HGSC) accounts for the vast majority (>70%) of ovarian cancer-associated deaths with minor therapeutic improvements. Among four proposed molecular subtypes of HGSC, the C5 subtype is distinguished by high proliferative potential and elevated immune evasion which is indicated by an unfavorable MHCI/PD-L1 ratio. However, the underlying key drivers of the C5 subtype remained elusive. Here we identify oncofetal RNA-binding proteins (RBPs) promoting the immune evasion of C5-HGSC. The IGF2 mRNA binding protein 1 (IGF2BP1) enhances expression of the E3 ligase MDM2, which induces degradation of IRF1 resulting in reduced MHCI presentation. Concomitantly, IGF2BP1 elevates PD-L1 synthesis by impairing its microRNA-directed silencing. This shifts the intra-tumoral MHCI/PD-L1 ratio, limits immune cell infiltration, and promotes evasion of tumor cells from cytotoxic T cells (CTLs) in human and syngeneic mouse models of ovarian cancer. The small molecule inhibitor BTYNB impairs IGF2BP1-directed regulation of MHCI/PD-L1 ratios, promotes CTL-directed killing as well as activation, and strongly synergizes with immune checkpoint inhibition (ICI) by Nivolumab in vitro and in vivo.
2025-10-28 | GSE285176 | GEO
Project description:High-grade serous ovarian cancer (HGSC) accounts for the vast majority (>70%) of ovarian cancer-associated deaths with minor therapeutic improvements. Among four proposed molecular subtypes of HGSC, the C5 subtype is distinguished by high proliferative potential and elevated immune evasion which is indicated by an unfavorable MHCI/PD-L1 ratio. However, the underlying key drivers of the C5 subtype remained elusive. Here we identify oncofetal RNA-binding proteins (RBPs) promoting the immune evasion of C5-HGSC. The IGF2 mRNA binding protein 1 (IGF2BP1) enhances expression of the E3 ligase MDM2, which induces degradation of IRF1 resulting in reduced MHCI presentation. Concomitantly, IGF2BP1 elevates PD-L1 synthesis by impairing its microRNA-directed silencing. This shifts the intra-tumoral MHCI/PD-L1 ratio, limits immune cell infiltration, and promotes evasion of tumor cells from cytotoxic T cells (CTLs) in human and syngeneic mouse models of ovarian cancer. The small molecule inhibitor BTYNB impairs IGF2BP1-directed regulation of MHCI/PD-L1 ratios, promotes CTL-directed killing as well as activation, and strongly synergizes with immune checkpoint inhibition (ICI) by Nivolumab in vitro and in vivo.
2025-10-28 | GSE285175 | GEO
Project description:High-grade serous ovarian cancer (HGSC) accounts for the vast majority (>70%) of ovarian cancer-associated deaths with minor therapeutic improvements. Among four proposed molecular subtypes of HGSC, the C5 subtype is distinguished by high proliferative potential and elevated immune evasion which is indicated by an unfavorable MHCI/PD-L1 ratio. However, the underlying key drivers of the C5 subtype remained elusive. Here we identify oncofetal RNA-binding proteins (RBPs) promoting the immune evasion of C5-HGSC. The IGF2 mRNA binding protein 1 (IGF2BP1) enhances expression of the E3 ligase MDM2, which induces degradation of IRF1 resulting in reduced MHCI presentation. Concomitantly, IGF2BP1 elevates PD-L1 synthesis by impairing its microRNA-directed silencing. This shifts the intra-tumoral MHCI/PD-L1 ratio, limits immune cell infiltration, and promotes evasion of tumor cells from cytotoxic T cells (CTLs) in human and syngeneic mouse models of ovarian cancer. The small molecule inhibitor BTYNB impairs IGF2BP1-directed regulation of MHCI/PD-L1 ratios, promotes CTL-directed killing as well as activation, and strongly synergizes with immune checkpoint inhibition (ICI) by Nivolumab in vitro and in vivo.
2025-10-28 | GSE234707 | GEO
Project description:Treatment of established lines and primary ovarian cancer cultures with Src and MEK inhibitors, saracatinib and selumetinib, respectively, showed target kinase inhibition and synergistic induction of apoptosis and cell cycle arrest in vitro and tumor inhibition in xenografts.
2018-03-28 | GSE112371 | GEO
Project description:Biliary tract carcinoma (BTC) has a poor prognosis due to limited treatment options. There is therefore urgent need to identify new targets and to design innovative therapeutic approaches. Among potential candidate molecules, we evaluated the non-receptor tyrosine kinase Src, observing promising antitumor effects of its small molecule inhibitor Saracatinib in BTC preclinical models. The presence of an active Src protein was investigated by immunohistochemistry in 19 surgical samples from BTC patients. Upon Saracatinib treatment, the phosphorylation of Src and of its downstream transducers was evaluated in the BTC cell lines TFK-1, EGI-1, HuH28 and TGBC1-TKB. The effect of Saracatinib on proliferation and migration was analyzed in these same cell lines, and its antitumor activity was essayed in EGI-1 mouse xenografts. Saracatinib-modulated transcriptome was profiled in EGI-1 cells and in tumor samples of the xenograft model. Src was activated in about 80% of the human BTC samples. In cultured BTC cell lines, low-dose Saracatinib counteracted the activation of Src and of its downstream effectors, increased the fraction of cells in G0/G1 phase, and inhibited cell migration. At high concentrations (median dose from 2.26 to 6.99 µM), Saracatinib was also capable of inhibiting BTC cell proliferation. In vivo, Saracatinib treatment resulted in delayed tumor growth, associated with an impaired vascular network. We here provide a demonstration that the targeted inhibition of Src kinase by Saracatinib is of therapeutic benefit in preclinical models of BTC. We propose our results as a basis for the design of Saracatinib-based clinical applications. EGI-1 cell line treated with Saracatinib at the dose of 10 µM vs EGI-1 cell line untreated; EGI-1 xenograft treated with Saracatinib at the dose of 25 mg/Kg/die vs EGI-1 xenograft untreated Transcriptional alteration mediated by Saracatinib in vitro and in vivo
2012-08-02 | E-GEOD-36622 | biostudies-arrayexpress
Project description:We sought to detect predictive markers related to a Src kinase inhibitor (saracatinib) sensitivity in ovarian cancer. Cell proliferation assays assigned 18 ovarian cancer cell lines to sensitive or resistant to this drug. Using baseline gene expression data from these 18 cell lines, we sought to identify differentially expressed genes correlated with saracatinib sensitivity. We also used SNP array data from 7 cell lines to detect differentically affected genomic locations.
2017-03-05 | GSE55628 | GEO
Project description:High-grade serous ovarian cancer (HGSC) accounts for the vast majority (>70%) of ovarian cancer-associated deaths with minor therapeutic improvements. Among four proposed molecular subtypes of HGSC, the C5 subtype is distinguished by high proliferative potential and elevated immune evasion which is indicated by an unfavorable MHCI/PD-L1 ratio. However, the underlying key drivers of the C5 subtype remained elusive. Here we identify oncofetal RNA-binding proteins (RBPs) promoting the immune evasion of C5-HGSC. The IGF2 mRNA binding protein 1 (IGF2BP1) enhances expression of the E3 ligase MDM2, which induces degradation of IRF1 resulting in reduced MHCI presentation. Concomitantly, IGF2BP1 elevates PD-L1 synthesis by impairing its microRNA-directed silencing. This shifts the intra-tumoral MHCI/PD-L1 ratio, limits immune cell infiltration, and promotes evasion of tumor cells from cytotoxic T cells (CTLs) in human and syngeneic mouse models of ovarian cancer. The small molecule inhibitor BTYNB impairs IGF2BP1-directed regulation of MHCI/PD-L1 ratios, promotes CTL-directed killing as well as activation, and strongly synergizes with immune checkpoint inhibition (ICI) by Nivolumab in vitro and in vivo.
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