HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis
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Date
2020-07-01Author
Palomo Irigoyen, Marta
Pérez Andrés, Encarni
Iruarrizaga Lejarreta, Marta
Barreira Manrique, Adrián
Tamayo Caro, Miguel
Vila Vecilla, Laura
Moreno Cugnon, Leire
Beitia, Nagore
Medrano, Daniela
Fernández Ramos, David
Lozano, Juan José
Okawa, Satoshi
Lavín, José L.
Martín Martín, Natalia
Sutherland, James D.
Guitiérez de Juan, Virginia
González López, Monika
Macías Cámara, Nuria
Mosén Ansorena, David
Laraba, Liyam
Hanemann, C. Oliver
Ercolano, Emanuela
Parkinson, David B.
Schultz, Christopher W.
Araúzo Bravo, Marcos J.
Ascensión, Alex M.
Gerovska, Daniela
Iribar López, Haizea
Pytel, Peter
Krastel, Philipp
Provenzani, Alessandro
Seneci, Pierfausto
Carrasco, Ruben D.
Del Sol, Antonio
Barrio Olano, María Rosa
Serra, Eduard
Lazaro, Conxi
Flanagan, Adrienne M.
Gorospe, Myriam
Ratner, Nancy
Aransay Bañares, Ana María
Varela Rey, Marta
Woodhoo, Ashwin
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Journal of Clinical Investigation 130(7) : 3848-3864 (2020)
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/beta-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.