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 5

Pharmacological inhibition of HuR blocks MPNST cell growth and metastasis in vitro and in vivo.

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Pharmacological inhibition of HuR blocks MPNST cell growth and metastasi...
(A and B) Pharmacological inhibition of HuR activity leads to a reduction in cell growth in MPNST cell lines ST88-14 and STS-26T, as determined by ATP luminescence, counts of cell numbers, clonogenic assays (foci), and anchorage-independent growth using soft agar assays. Graphs represent absorbance of crystal violet–stained colonies for clonogenic assays and number of colonies in soft agar assays. Data are normalized to DMSO-treated and are presented as mean ± SEM. Each data point represents 1 independent experiment; 1-way ANOVA with Tukey’s multiple-comparisons test. (C–E) Pharmacological inhibition of HuR activity by MS-444 promotes tumor regression in vivo. (C) Pictures of tumors from nude mice injected with STS-26T MPNST cells after vehicle or MS-444 treatment. Scale bar: 10 mm. (D) Graph showing weight of excised tumors for both groups of mice. (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 pharmacological inhibition. Each data point represents 1 mouse. Data are presented as mean ± SEM; 2-tailed unpaired Mann-Whitney U test. (F–H) Pharmacological inhibition of HuR activity by MS-444 prevents growth of established lung metastatic nodules in vivo. (F) Representative pictures of lung histology from nude mice injected with STS-26T MPNST cells after vehicle or MS-444 treatment. Scale bar: 5 mm. (G and H) Number of lung metastases (G) and lung metastatic area, expressed as a percentage of total lung area (H), were quantified. Each data point represents 1 mouse. Data are presented as mean ± SEM; 2-tailed unpaired Mann-Whitney U test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.