A kinome-wide high-content siRNA screen identifies MEK5–ERK5 signaling as critical for breast cancer cell EMT and metastasis

Pavan, Simona; Meyer-Schaller, Nathalie; Diepenbruck, Maren; Kalathur, Ravi Kiran Reddy; Saxena, Mohit; Christofori, Gerhard

doi:10.1038/s41388-018-0270-8

Cited by 45 publications

(40 citation statements)

References 65 publications

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“…COX2 overexpression is associated with progression in multiple cancers, and COX2 inhibitors have shown promising therapeutic effects in clinical trials [39,40]. Furthermore, both GRB2 and MEK5/ERK5 are commonly overexpressed in breast cancer and associated with poor overall survival, and targeting of these proteins/ pathways is shown to suppress breast cancer progression [41][42][43]. Thus, downregulation of COX2, GRB2 and MEK5 as seen in the ATX-101/AEE788 combination treatment supports the phenotype observed in this pre-clinical breast cancer model.…”

Section: Discussionmentioning

confidence: 99%

Targeting the non-canonical roles of PCNA modifies and increases the response to targeted anti-cancer therapy

et al. 2019

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Receptor tyrosine kinases (RTKs), such as HER2 and/or EGFR are important therapeutic targets in multiple cancer cells. Low and/or short response to targeted therapies are often due to activation of compensatory signaling pathways, and therefore a combination of kinase inhibitors with other anti-cancer therapies have been proposed as promising strategies. PCNA is recently shown to have non-canonical cytosolic roles, and targeting PCNA with a cell-penetrating peptide containing the PCNA-interacting motif APIM is shown to mediate changes in central signaling pathways such as PI3K/Akt and MAPK, acting downstream of multiple RTKs. In this study, we show how targeting PCNA increased the anti-cancer activity of EGFR/ HER2/VEGFR inhibition in vitro as well as in vivo. The combination treatment resulted in reduced tumor load and increased the survival compared to either single agent treatments. The combination treatment affected multiple cellular signaling responses not seen by EGFR/HER2/VEGFR inhibition alone, and changes were seen in pathways determining protein degradation, ER-stress, apoptosis and autophagy. Our results suggest that targeting the non-canonical roles of PCNA in cellular signaling have the potential to improve targeted therapies.

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Section: Discussionmentioning

confidence: 99%

Targeting the non-canonical roles of PCNA modifies and increases the response to targeted anti-cancer therapy

et al. 2019

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“…To identify all (co)TFs that are required for EMT irrespective of their differential expression, we employed a microscopy-based EMT screen that we have previously used to screen for pharmacological EMT inhibitors as well as for kinases and phosphatases required for EMT (Pavan et al, 2018). This screen is based on cytoskeleton remodeling events occurring during EMT and enabling cell migration (Figure 2A).…”

Section: High-content Microscopy Screen For (Co)tfs Essential For Emtmentioning

confidence: 99%

A Hierarchical Regulatory Landscape during the Multiple Stages of EMT

et al. 2019

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Highlights d A large number of TFs and miRNAs are critical for EMT to occur d EMT involves a temporal hierarchy of transcriptional networks d Reciprocal networks between TFs and between TFs and miRNAs regulates EMT d These analyses serve as a resource for exploring gene regulation during EMT SUMMARYEpithelial-mesenchymal transition (EMT) enables cells to gain migratory and invasive features underlined by major transcriptional and epigenetic reprogramming. However, most studies have focused on the endpoints of the EMT process, and the epistatic hierarchy of the transcriptional networks underlying EMT has remained elusive. We have used a siRNAbased, functional high-content microscopy screen to identify 46 (co)transcription factors ((co)TFs) and 13 miRNAs critically required for EMT in normal murine mammary gland (NMuMG) cells. We compared dynamic gene expression during EMT kinetics and used functional perturbation of critical (co)TFs and miRNAs to identify groups and networks of EMT genes. Computational analysis as well as functional validation experiments revealed interaction networks between TFs and miRNAs and delineated the hierarchical and functional interactions of multiple EMT regulatory networks in NMuMG cells.

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“…Previous studies have identified target genes for inhibiting migration and/or invasion ability of cancer cells through library screening. Pavan et al (66) developed a system combining RNAi library screening with a microscopy-based high-throughput quantitative analysis to identify a signaling pathway contributing to EMT in breast cancer. The group identified 59 genes whose inhibition suppressed transforming growth factor β-induced EMT in immortalized epithelial normal murine mammary gland cells.…”

Section: Dropout Viability Screening Under Drug Treatmentmentioning

confidence: 99%

“…The group identified 59 genes whose inhibition suppressed transforming growth factor β-induced EMT in immortalized epithelial normal murine mammary gland cells. In addition, Pavan et al (66) focused on MEK5 and ERK5 belonging to the same signaling pathway and demonstrated the potential of targeting MEK5 and ERK5 as an anti-metastatic mechanism. Another study used migration ability as a phenotype for functional screening, identifying genes contributing to migration in glioblastoma, a highly invasive cancer (67).…”

Section: Dropout Viability Screening Under Drug Treatmentmentioning

confidence: 99%

Phenotypic screening using large‑scale genomic libraries to identify drug targets for the treatment of cancer (Review)

Sato

2020

Oncol Lett

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During malignant progression to overt cancer cells, normal cells accumulate multiple genetic and non-genetic changes, which result in the acquisition of various oncogenic properties, such as uncontrolled proliferation, drug resistance, invasiveness, anoikis-resistance, the ability to bypass oncogene-induced senescence and cancer stemness. To identify potential novel drug targets contributing to these malignant phenotypes, researchers have performed large-scale genomic screening using various in vitro and in vivo screening models and identified numerous promising cancer drug target genes. However, there are issues with these identified genes, such as low reproducibility between different datasets. In the present study, the recent advances in the functional screening for identification of cancer drug target genes are summarized, and current issues and future perspectives are discussed.

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A kinome-wide high-content siRNA screen identifies MEK5–ERK5 signaling as critical for breast cancer cell EMT and metastasis

Cited by 45 publications

References 65 publications

Targeting the non-canonical roles of PCNA modifies and increases the response to targeted anti-cancer therapy

Targeting the non-canonical roles of PCNA modifies and increases the response to targeted anti-cancer therapy

A Hierarchical Regulatory Landscape during the Multiple Stages of EMT

Phenotypic screening using large‑scale genomic libraries to identify drug targets for the treatment of cancer (Review)

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