Document Type
Article
Publication Date
7-1-2020
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/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.
Recommended Citation
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; de Juan, Virginia Guitiérez; Gonzalez-Lopez, Monika; Macías-Cámara, Nuria; Mosén-Ansorena, David; Laraba, Liyam; Hanemann, C Oliver; Ercolano, Emanuela; Parkinson, David B; Schultz, BS, Christopher W.; Araúzo-Bravo, Marcos J; Ascensión, Alex M; Gerovska, Daniela; Iribar, Haizea; Izeta, Ander; Pytel, Peter; Krastel, Philipp; Provenzani, Alessandro; Seneci, Pierfausto; Carrasco, Ruben D; Del Sol, Antonio; Martinez-Chantar, María Luz; Barrio, Rosa; Serra, Eduard; Lazaro, Conxi; Flanagan, Adrienne M; Gorospe, Myriam; Ratner, Nancy; Aransay, Ana M; Carracedo, Arkaitz; Varela-Rey, Marta; and Woodhoo, Ashwin, "HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis" (2020). Department of Surgery Faculty Papers. Paper 184.
https://jdc.jefferson.edu/surgeryfp/184
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
32315290
Language
English
Comments
This article is the author’s final published version in The Journal of clinical investigation, Volume 130, Issue 7, July 2020, Pages 3848-3864.
The published version is available at https://doi.org/10.1172/JCI130379. Copyright © Palomo-Irigoyen