HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis
Marta Palomo-Irigoyen, … , Marta Varela-Rey, Ashwin Woodhoo
Marta Palomo-Irigoyen, … , Marta Varela-Rey, Ashwin Woodhoo
Published April 21, 2020
Citation Information: J Clin Invest. 2020;130(7):3848-3864. https://doi.org/10.1172/JCI130379.
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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 4

HuR promotes MPNST metastasis in vivo.

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HuR promotes MPNST metastasis in vivo. (A–C) Constitutive HuR silencing ...
(A–C) Constitutive HuR silencing prevents lung metastasis of STS-26T MPNST cells. (A) Schematic representation of lung metastasis experiments. shCtrl (n = 6) or shHuR#1-expressing (n = 7) STS-26T MPNST cells were injected in the tail vein of nude mice, and lung architecture analyzed by H&E staining 4 weeks later. Representative pictures of lung histology are shown. Scale bar: 2 mm. (B and C) Number of lung metastases (B) and lung metastatic area, expressed as a percentage of total lung area (C), were quantified by H&E histology. (D–F) Inducible HuR silencing prevents growth of established lung metastatic nodules. (D) Schematic representation of experiments. sh iCtrl or sh iHuR–expressing STS-26T MPNST cells were injected in the tail vein of nude mice. A group of mice (n = 3 for each condition) was sacrificed at 2 weeks (W2) to analyze basal formation of lung metastases, and the rest fed with normal diet (–Dox) or doxycycline diet to induce expression of shRNAs (+Dox) for a further 4 weeks before analysis of lung histology by H&E staining. Representative pictures of lung histology for the following groups are shown: sh iCtrl with normal diet (sh iCtrl; –Dox) n = 5; sh iCtrl with doxycycline diet (sh iCtrl; +Dox) n = 5, sh iHuR with normal diet (sh iHuR; –Dox) n = 5, sh iHuR with doxycycline diet (sh iHuR; +Dox) n = 5. Scale bar: 2 mm. (E and F) Number of lung metastases (E) and lung metastatic area, expressed as a percentage of total lung area (F), were quantified. Each data point represents 1 mouse. Data are presented as mean ± SEM; 2-tailed unpaired Mann-Whitney U test (B and C); 1-way ANOVA with Holm-Šidák multiple-comparisons test (E and F). *P < 0.05; **P < 0.01.