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HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis.

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/?-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.

SUBMITTER: Palomo-Irigoyen M

PROVIDER: S-EPMC7324187 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis.

Palomo-Irigoyen Marta M Pérez-Andrés Encarni E Iruarrizaga-Lejarreta Marta M Barreira-Manrique Adrián A Tamayo-Caro Miguel M Vila-Vecilla Laura L Moreno-Cugnon Leire L Beitia Nagore N Medrano Daniela D Fernández-Ramos David D Lozano Juan José JJ Okawa Satoshi S Lavín José L JL Martín-Martín Natalia N Sutherland James D JD de Juan Virginia Guitiérez VG Gonzalez-Lopez Monika M Macías-Cámara Nuria N Mosén-Ansorena David D Laraba Liyam L Hanemann C Oliver CO Ercolano Emanuela E Parkinson David B DB Schultz Christopher W CW Araúzo-Bravo Marcos J MJ Ascensión Alex M AM Gerovska Daniela D Iribar Haizea H Izeta Ander A Pytel Peter P Krastel Philipp P Provenzani Alessandro A Seneci Pierfausto P Carrasco Ruben D RD Del Sol Antonio A Martinez-Chantar María Luz ML Barrio Rosa R Serra Eduard E Lazaro Conxi C Flanagan Adrienne M AM Gorospe Myriam M Ratner Nancy N Aransay Ana M AM Carracedo Arkaitz A Varela-Rey Marta M Woodhoo Ashwin A

The Journal of clinical investigation 20200701 7

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-ass ...[more]

PMID: 32315290

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Project description:The heterogeneity of soft tissue sarcoma (STS) represents a major challenge for the development of effective therapeutics. Comprised of over 50 different histology subtypes of various etiologies, STS subsets are further characterized as either karyotypically simple or complex. Due to the number of genetic anomalies associated with genetically complex STS, development of therapies demonstrating potency against this STS cluster is especially challenging and yet greatly needed. Verticillin A is a small molecule natural product with demonstrated anticancer activity; however, the efficacy of this agent has never been evaluated in STS. Therefore, the goal of this study was to explore verticillin A as a potential STS therapeutic. We performed survival (MTS) and clonogenic analyses to measure the impact of this agent on the viability and colony formation capability of karyotypically complex STS cell lines: malignant peripheral nerve sheath tumor (MPNST) and leiomyosarcoma (LMS). The in vitro effects of verticillin A on apoptosis were investigated through annexin V/PI flow cytometry analysis and by measuring fluorescently-labeled cleaved caspase 3/7 activity. The impact on cell cycle progression was assessed via cytometric measurement of propidium iodide intercalation. In vivo studies were performed using MPNST xenograft models. Tumors were processed and analyzed using immunohistochemistry (IHC) for verticillin A effects on growth (Ki67) and apoptosis (cleaved caspase 3). Treatment with verticillin A resulted in decreased STS growth and an increase in apoptotic levels after 24 h. 100 nM verticillin A induced significant cellular growth abrogation after 24 h (96.7, 88.7, 72.7, 57, and 39.7% reduction in LMS1, S462, ST88, SKLMS1, and MPNST724, respectively). We observed no arrest in cell cycle, elevated annexin, and a nearly two-fold increase in cleaved caspase 3/7 activity in all MPNST and LMS cell lines. Control normal human Schwann (HSC) and aortic smooth muscle (HASMC) cells displayed higher tolerance to verticillin A treatment compared to sarcoma cell lines, although toxicity was seen in HSC at the highest treatment dose. In vivo studies mirrored the in vitro results: by day 11, tumor size was significantly reduced in MPNST724 xenograft models with treatment of 0.25 and 0.5 mg/kg verticillin A. Additionally, IHC assessment of tumors demonstrated increased cleaved caspase 3 and decreased proliferation (Ki67) following treatment with verticillin A. Advancement in the treatment of karyotypically complex STS is confounded by the high level of genetic abnormalities found in these diseases. Consequently, the identification and investigation of novel therapies is greatly needed. Our data suggest that verticillin A selectively inhibits MPNST and LMS growth via induction of apoptosis while exhibiting minimal to moderate effects on normal cells, pointing to verticillin A as a potential treatment for MPNST and LMS, after additional preclinical validation.

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HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis.

Publications

HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis.

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