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.
| Original language | English |
|---|---|
| Pages (from-to) | 3848-3864 |
| Number of pages | 17 |
| Journal | Journal of Clinical Investigation |
| Volume | 130 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - 1 Jul 2020 |
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In: Journal of Clinical Investigation, Vol. 130, No. 7, 01.07.2020, p. 3848-3864.
Research output: Contribution to journal › Article › Research › peer-review
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 - Oliver Hanemann, C.
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 - Sol, Antonio Del
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
N1 - Funding Information: This work was funded by grants to AW from the Spanish Association Against Cancer (AECC; JP Vizcaya); Spanish Ministry of Science, Innovation and Universities (MCIU)/Agencia Estatal de Investigación (AEI)/European Regional Development Fund (FEDER), European Union (EU) (Subprograma Ramon y Cajal RYC2010-06901; Proyectos Retos Investigación RTI2018-097503-B-I00, SAF2015-65360-R; Proyectos Explora Ciencia SAF2015-72416-EXP; Proyectos Europa Excelencia SAF2015-62588-ERC); the BBVA Foundation; Basque Department of Industry, Tourism and Trade (Elkartek) and Education (PI2013-46); Fundación Vasca de Innovación e Investigación Sanitarias EiTB Maratoia (BIO13/CI/015); the Neurofibromatosis Therapeutic Acceleration Program; and the European Research Council (consolidator grant under the EU’s Horizon 2020 research and innovation programme; grant agreement 865157). MVR is grateful for the support of a 2017 Leonardo Grant for Researchers and Cultural Creators (BBVA Foundation), Acción Estratégica Ciber Emergentes 2018 (Ciberehd-ISCIII), and Gil-ead Sciences International Research Scholars Program in Liver Disease. The work of AC is supported by the Basque Department of Industry, Tourism and Trade (Elkartek) and Education (IKERTALDE IT1106-16); the BBVA Foundation; the MCIU/ AEI (SAF2016-79381-R [FEDER/EU]; Severo Ochoa Excellence Accreditation SEV-2016-0644; Excellence Networks SAF2016-81975-REDT); the European Training Networks Project (H2020-MSCA-ITN-308 2016 721532); the AECC (IDEAS175CARR, GCTRA18006CARR); La Caixa Foundation (HR17-00094); and the European Research Council (Starting Grant 336343, PoC 754627). MG was supported by the Intramural Research Program of the National Institute on Aging, NIH. MPI is grateful for the support of the Basque Government of Education fellowship. MTC is grateful for the support of “Ayudas para contratos pre-doctorales para la formacion de doctores” (MCIU/AEI/FEDER, EU). COH acknowledges funding from Brain Tumour Research. RB acknowledges MCIU/AEI/FEDER, EU (BFU2014-52282-P and BFU2017-84653-P). ES and CL are supported by the Carlos III National Health Institute funded by FEDER funds — a way to build Europe (CIBERONC) and the Government of Catalonia (2017SGR496). MLM-C acknowledges support from MCIU/ AEI/FEDER, EU (SAF2017-87301-R); Asociación Española Contra El Cáncer (AECC); AECC Canceres Raros; BBVA Bio-medicina (UMBRELLA); and La CAIXA Foundation (LCF/PR/ HP17/52190004). AP was supported by Associazione Italiana Ricerca sul Cancro (AIRC; IG 2018 Id.21548). CIBERehd is funded by the Instituto de Salud Carlos III. We thank MCIU for the Severo Ochoa Excellence Accreditation (SEV-2016-0644). Funding Information: This work was funded by grants to AW from the Spanish Association Against Cancer (AECC; JP Vizcaya); Spanish Ministry of Science, Innovation and Universities (MCIU)/Agencia Estatal de Investigaci?n (AEI)/European Regional Development Fund (FEDER), European Union (EU) (Subprograma Ramon y Cajal RYC2010-06901; Proyectos Retos Investigaci?n RTI2018-097503-B-I00, SAF2015-65360-R; Proyectos Explora Ciencia SAF2015-72416-EXP; Proyectos Europa Excelencia SAF2015-62588-ERC); the BBVA Foundation; Basque Department of Industry, Tourism and Trade (Elkartek) and Education (PI2013-46); Fundaci?n Vasca de Innovaci?n e Investigaci?n Sanitarias EiTB Maratoia (BIO13/CI/015); the Neurofibromatosis Therapeutic Acceleration Program; and the European Research Council (consolidator grant under the EU's Horizon 2020 research and innovation programme; grant agreement 865157). MVR is grateful for the support of a 2017 Leonardo Grant for Researchers and Cultural Creators (BBVA Foundation), Acci?n Estrat?gica Ciber Emergentes 2018 (Ciberehd-ISCIII), and Gilead Sciences International Research Scholars Program in Liver Disease. The work of AC is supported by the Basque Department of Industry, Tourism and Trade (Elkartek) and Education (IKERTALDE IT1106-16); the BBVA Foundation; the MCIU/ AEI (SAF2016-79381-R [FEDER/EU]; Severo Ochoa Excellence Accreditation SEV-2016-0644; Excellence Networks SAF2016-81975-REDT); the European Training Networks Project (H2020-MSCA-ITN-308 2016 721532); the AECC (IDEAS175CARR, GCTRA18006CARR); La Caixa Foundation (HR17-00094); and the European Research Council (Starting Grant 336343, PoC 754627). MG was supported by the Intramural Research Program of the National Institute on Aging, NIH. MPI is grateful for the support of the Basque Government of Education fellowship. MTC is grateful for the support of ?Ayudas para contratos predoctorales para la formacion de doctores? (MCIU/AEI/FEDER, EU). COH acknowledges funding from Brain Tumour Research. RB acknowledges MCIU/AEI/FEDER, EU (BFU2014-52282-P and BFU2017-84653-P). ES and CL are supported by the Carlos III National Health Institute funded by FEDER funds ' a way to build Europe (CIBERONC) and the Government of Catalonia (2017SGR496). MLM-C acknowledges support from MCIU/ AEI/FEDER, EU (SAF2017-87301-R); Asociaci?n Espa?ola Contra El C?ncer (AECC); AECC Canceres Raros; BBVA Biomedicina (UMBRELLA); and La CAIXA Foundation (LCF/PR/ HP17/52190004). AP was supported by Associazione Italiana Ricerca sul Cancro (AIRC; IG 2018 Id.21548). CIBERehd is funded by the Instituto de Salud Carlos III. We thank MCIU for the Severo Ochoa Excellence Accreditation (SEV-2016-0644). Publisher Copyright: Copyright: © 2020, Palomo-Irigoyen et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
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.
UR - http://www.scopus.com/inward/record.url?scp=85087469818&partnerID=8YFLogxK
U2 - 10.1172/JCI130379
DO - 10.1172/JCI130379
M3 - Article
C2 - 32315290
AN - SCOPUS:85087469818
SN - 0021-9738
VL - 130
SP - 3848
EP - 3864
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 7
ER -