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 3

HuR promotes MPNST cell growth in vivo.

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HuR promotes MPNST cell growth in vivo. (A and B) Constitutive HuR silen...
(A and B) Constitutive HuR silencing prevents tumor formation in vivo. (A) Schematic representation of xenotransplantation experiments. (B) Representative pictures of tumors from nude mice injected with shCtrl or shHuR#1 STS-26T MPNST cells 5 weeks after transplant (n = 5) for each condition. Scale bar: 5 mm. (C–F) Inducible HuR silencing promotes tumor regression in vivo. (C) Schematic representation of xenotransplantation experiments using inducible HuR-silencing strategy. (D) Representative pictures of tumors from nude mice injected with sh iCtrl or sh iHuR STS-26T MPNST cells on left and right flank, respectively, at 20 days after injection (day 20) and 10 days later (day 30), with (+ Dox) or without doxycycline diet (– Dox). (E) Waterfall plot showing change in tumor volume (represented as log2 fold change) of individual tumors formed at 20 days after transplant and after 10 days with or without doxycycline treatment for each of 4 groups of mice. sh iCtrl (–Dox) n = 7; sh iCtrl (+Dox) n = 7; sh iHuR (–Dox) n = 7; sh iHuR (+Dox) n = 7. (F) Graph showing weight of excised tumors for the 4 groups of mice. Each data point represents 1 mouse; 1-way ANOVA with Tukey’s multiple-comparisons test. **P < 0.01; ***P < 0.001; ****P < 0.0001.