HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis
Marta Palomo-Irigoyen, et al.
Marta Palomo-Irigoyen, et al.
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Research Article Cell biology Oncology

HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis

Abstract

Cancer cells can develop a strong addiction to discrete molecular regulators, which control the aberrant gene expression programs that drive and maintain the cancer phenotype. Here, we report the identification of the RNA-binding protein HuR/ELAVL1 as a central oncogenic driver for malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive sarcomas that originate from cells of the Schwann cell lineage. HuR was found to be highly elevated and bound to a multitude of cancer-associated transcripts in human MPNST samples. Accordingly, genetic and pharmacological inhibition of HuR had potent cytostatic and cytotoxic effects on tumor growth, and strongly suppressed metastatic capacity in vivo. Importantly, we linked the profound tumorigenic function of HuR to its ability to simultaneously regulate multiple essential oncogenic pathways in MPNST cells, including the Wnt/β-catenin, YAP/TAZ, RB/E2F, and BET pathways, which converge on key transcriptional networks. Given the exceptional dependency of MPNST cells on HuR for survival, proliferation, and dissemination, we propose that HuR represents a promising therapeutic target for MPNST treatment.

Authors

Marta Palomo-Irigoyen, Encarni Pérez-Andrés, Marta Iruarrizaga-Lejarreta, Adrián Barreira-Manrique, Miguel Tamayo-Caro, Laura Vila-Vecilla, Leire Moreno-Cugnon, Nagore Beitia, Daniela Medrano, David Fernández-Ramos, Juan José Lozano, Satoshi Okawa, José L. Lavín, Natalia Martín-Martín, James D. Sutherland, Virginia Guitiérez de Juan, Monika Gonzalez-Lopez, Nuria Macías-Cámara, David Mosén-Ansorena, Liyam Laraba, C. Oliver Hanemann, Emanuela Ercolano, David B. Parkinson, Christopher W. Schultz, Marcos J. Araúzo-Bravo, Alex M. Ascensión, Daniela Gerovska, Haizea Iribar, Ander Izeta, Peter Pytel, Philipp Krastel, Alessandro Provenzani, Pierfausto Seneci, Ruben D. Carrasco, Antonio Del Sol, María Luz Martinez-Chantar, Rosa Barrio, Eduard Serra, Conxi Lazaro, Adrienne M. Flanagan, Myriam Gorospe, Nancy Ratner, Ana M. Aransay, Arkaitz Carracedo, Marta Varela-Rey, Ashwin Woodhoo

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Figure 2

HuR is bound to key targets in human MPNSTs.

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HuR is bound to key targets in human MPNSTs. (A) Volcano plots show enri...
(A) Volcano plots show enrichment of transcripts most significantly bound to HuR compared with control IgG in neurofibromas (left) (n = 8) and MPNSTs (right) (n = 12) obtained from Stanmore Musculoskeletal Biobank. Red or blue dots, fold change >1.5; adjusted P value < 0.05. Venn diagram shows overlap between putative HuR mRNA targets from neurofibromas and MPNSTs. (B) GSEA analysis of putative HuR mRNA targets in MPNSTs for MSigDB hallmarks. The top 20 gene sets (FDR iQ values < 0.1) are plotted relative to normalized enrichment score (NES). Circles denote the number of enriched genes in each category. (C and D) GSEA plots of HuR IP and control IgG IP for key cancer traits (C) and oncogenic pathways (D) in MPNSTs.