TY - JOUR
T1 - HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis
AU - Palomo-Irigoyen, Marta
AU - Pérez-Andrés, Encarni
AU - Iruarrizaga-Lejarreta, Marta
AU - Barreira-Manrique, Adrián
AU - Tamayo-Caro, Miguel
AU - Vila-Vecilla, Laura
AU - Moreno-Cugnon, Leire
AU - Beitia, Nagore
AU - Medrano, Daniela
AU - Fernández-Ramos, David
AU - Lozano, Juan José
AU - Okawa, Satoshi
AU - Lavín, José L
AU - Martín-Martín, Natalia
AU - Sutherland, James D
AU - de Juan, Virginia Guitiérez
AU - Gonzalez-Lopez, Monika
AU - Macías-Cámara, Nuria
AU - Mosén-Ansorena, David
AU - Laraba, Liyam
AU - Hanemann, C Oliver
AU - Ercolano, Emanuela
AU - Parkinson, David B
AU - Schultz, Christopher W
AU - Araúzo-Bravo, Marcos J
AU - Ascensión, Alex M
AU - Gerovska, Daniela
AU - Iribar, Haizea
AU - Izeta, Ander
AU - Pytel, Peter
AU - Krastel, Philipp
AU - Provenzani, Alessandro
AU - Seneci, Pierfausto
AU - Carrasco, Ruben D
AU - Del Sol, Antonio
AU - Martinez-Chantar, María Luz
AU - Barrio, Rosa
AU - Serra, Eduard
AU - Lazaro, Conxi
AU - Flanagan, Adrienne M
AU - Gorospe, Myriam
AU - Ratner, Nancy
AU - Aransay, Ana M
AU - Carracedo, Arkaitz
AU - Varela-Rey, Marta
AU - Woodhoo, Ashwin
PY - 2020/7/1
Y1 - 2020/7/1
N2 - 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.
AB - 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.
KW - Animals
KW - Carcinogenesis/genetics
KW - Cell Line, Tumor
KW - Cell Proliferation
KW - ELAV-Like Protein 1/genetics
KW - Humans
KW - Mice
KW - Neoplasm Metastasis
KW - Neoplasm Proteins/genetics
KW - Nerve Sheath Neoplasms/genetics
KW - Signal Transduction
U2 - 10.1172/JCI130379
DO - 10.1172/JCI130379
M3 - Article
C2 - 32315290
SN - 0021-9738
VL - 130
SP - 3848
EP - 3864
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 7
ER -
