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 tumours (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 tumour growth, and strongly supressed 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 proteins, 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.
Marta Palomo-Irigoyen, Encarnación Pérez-Andrés, Marta Iruarrizaga-Lejarreta, Adrián Barreira Manrique, Miguel Tamayo-Caro, Laura Vila-Vecilla, Leire Moreno-Cugnon, Nagore Beitia Telletxea, Daniela Medrano, David Fernández-Ramos, Juan-Jose Lozano, Satoshi Okawa, José Luis Lavín, Natalia Martin-Martin, James D. Sutherland, Virginia Gutiérrez-de Juan, Monika Gonzalez-Lopez, Nuria Macias-Camara, 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, Maria L. Martinez Chantar, Rosa Barrio, Eduard Serra, Conxi Lázaro, Adrienne M. Flanagan, Myriam Gorospe, Nancy Ratner, Arkaitz Carracedo, Ana María Aransay, Marta Varela-Rey, Ashwin Woodhoo