Gene Regulatory Network in Schwann cell Disorders

Zusammenfassung

Cancer cells can develop a strong addiction to discrete molecular regulators, which control the aberranttranscription programs that drive and maintain the cancer phenotype. Here, we report the identificationof the RNA-binding protein HuR as a central oncogenic driver for malignant peripheral nerve sheathtumours (MPNSTs), which are highly aggressive sarcomas. We show HuR was bound to a multitude ofcancer-associated transcripts in human MPNST samples. Accordingly, genetic and pharmacologicalinhibition of HuR had potent cytostatic and cytotoxic effects on tumour growth, and strongly supressedmetastatic capacity in vivo. Importantly, we linked the profound tumorigenic function of HuR to itsability to simultaneously regulate multiple essential oncogenic pathways in MPNST cellls, including theWnt/ß-Catenin, YAP/TAZ, Rb-E2F and BET proteins, which converge on key transcriptional networks.Regulating survival, proliferation, and dissemination. Therefore, we propose HuR represents an idealtherapeutic target for MPNST treatment. Peripheral nervous system involvement has also beenobserved in Lyme disease-assicated clinical manifestations, which is the most common arthropod-borneinfectious disease in temperate regions. It is caused by infection with the spirochete Borreliaburgdorferi, which is transmitted by a tick bite. Here, we identified Schwann cells as the new targets ofB. burgdorferi, leading to demyelination in the absence of immune cells. We suggest that B. burgdorferiregulates intracellular signaling pathways, including Wnt/ß-Catenin, to strongly repress myelin gene andprotein expression, throwing light on one of the most intriguing pathological features of Lyme disease.