Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and is highly resistant to current treatments. ESCC harbors a subpopulation of cells exhibiting cancer stem-like cell (CSC) properties that contribute to therapeutic resistance including radioresistance, but the molecular mechanisms in ESCC CSCs are currently unknown. Here, we report that ribosomal S6 protein kinase 4 (RSK4) plays a pivotal role in promoting CSC properties and radioresistance in ESCC. RSK4 was highly expressed in ESCC CSCs and associated with radioresistance and poor survival in ESCC patients. RSK4 was found to be a direct downstream transcriptional target of ΔNp63α, the main p63 isoform, which is frequently amplified in ESCC. RSK4 activated the β-catenin signaling pathway through direct phosphorylation of GSK-3β Ser9. Pharmacologic inhibition of RSK4 effectively reduced CSC properties and improves radiosensitivity in both nude mice and patient-derived xenograft models. Collectively, our results strongly suggest that the ΔNp63α-RSK4-GSK-3β axis plays a key role in driving CSC properties and radioresistance in ESCC, indicating that RSK4 is a promising therapeutic target for ESCC treatment.
Mingyang Li, Linni Fan, Donghui Han, Zhou Yu, Jing Ma, Yixiong Liu, Peifeng Li, Danhui Zhao, Jia Chai, Lei Jiang, Shiliang Li, Juanjuan Xiao, Qiuhong Duan, Jing Ye, Mei Shi, Yongzhan Nie, Kai-Chun Wu, Dezhong Joshua Liao, Yu Shi, Yan Wang, Qingguo Yan, Shuangping Guo, Xiu-Wu Bian, Feng Zhu, Jian Zhang, Zhe Wang
This Viewpoint calls on investigators that are developing and testing therapeutic and prophylactic approaches for COVID-19 to design studies that are inclusive of male-female differences.
Evelyne Bischof, Jeannette Wolfe, Sabra L. Klein
Haploinsufficiency of factors governing genome stability underlies hereditary breast and ovarian cancer. Homologous recombination (HR) repair is a major pathway disabled in these cancers. With the aim of identifying new candidate genes, we examined early onset breast cancer patients negative for BRCA1 and BRCA2 pathogenic variants. Here, we focused on CtIP (RBBP8 gene) that mediates HR repair through the end-resection of DNA double-strand breaks (DSB). Notably, the patients exhibited a number of rare germline RBBP8 variants, and functional analysis revealed that these variants did not affect DNA DSB end-resection efficiency. However, expression of a subset of variants led to deleterious nucleolytic degradation of stalled DNA replication forks in a manner similar to cells lacking BRCA1 or BRCA2. In contrast to BRCA1 and BRCA2, CtIP deficiency promoted the helicase-driven destabilization of RAD51 nucleofilaments at damaged DNA replication forks. Taken together, our work identifies CtIP as a critical regulator of DNA replication fork integrity, which when compromised, may predispose to the development of early onset breast cancer.
Reihaneh Zarrizi, Martin R. Higgs, Karolin Voßgröne, Maria Rossing, Birgitte Bertelsen, Muthiah Bose, Arne N. Kousholt, Heike I. Rösner, Bent Ejlertsen, Grant S. Stewart, Finn Cilius Nielsen, Claus Sørensen
Several missense mutations in the orphan transporter FLVCR2 have been reported in Fowler syndrome. Affected subjects exhibit signs of severe neurological defects. We identified the mouse ortholog Mfsd7c as a gene, which is expressed in the blood brain barrier. Here, we report the characterizations of Mfsd7c knockout (KO) mice and compare it to phenotypic findings in humans with bi-allelic FLVCR2 mutations. Global KO of Mfsd7c in mice resulted in late gestation lethality, likely due to central nervous system (CNS) phenotypes. We found that the angiogenic growth of CNS blood vessels in the brain of Mfsd7c KO embryos was inhibited in cortical ventricular zones and ganglionic eminences. Vascular tips were dilated and fused resulting in glomeruloid vessels. Nonetheless, CNS blood vessels were intact without haemorrhage. Both embryos and humans with bi-allelic FLVCR2 mutations exhibited reduced cerebral cortical layers, enlargement of the cerebral ventricles, and microcephaly. Transcriptomic analysis of Mfsd7c knockout (KO) embryonic brains revealed upregulation of genes involved in glycolysis and angiogenesis. The Mfsd7c KO brain exhibited hypoxia and neuronal cell death. Our results indicate MFSD7c is required for the normal growth of CNS blood vessels and ablation of this gene results in microcephaly-associated vasculopathy in mice and humans.
Pazhanichamy Kalailingam, Kai Qi Wang, Xiu Ru Toh, Toan Q. Nguyen, Madhuvanthi Chandrakanthan, Zafrul Hasan, Clair Habib, Aharon Schif, Francesca Clementina Radio, Bruno Dallapiccola, Karin Weiss, Long N. Nguyen
Fowler syndrome is a rare autosomal recessive brain vascular disorder caused by mutation in FLVCR2 in humans. The disease occurs during a critical period of brain vascular development, is characterized by glomeruloid vasculopathy and hydrocephalus, and is almost invariably prenatally fatal. Here, we sought to gain insights into the process of brain vascularization and the pathogenesis of Fowler Syndrome by inactivating Flvcr2 in mice. We show that Flvcr2 is necessary for angiogenic sprouting in the brain, but surprisingly dispensable for maintaining the blood brain barrier. Endothelial cells lacking Flvcr2 have altered expression of angiogenic factors, fail to adopt tip-cell properties and display reduced sprouting leading to vascular malformations similar to those seen in humans with Fowler Syndrome. Brain hypo-vascularization is associated with hypoxia and tissue infarction, ultimately causing hydrocephalus and death of mutant animals. Strikingly, despite severe vascular anomalies and brain tissue infarction, the blood-brain barrier is maintained in Flvcr2 mutant mice. Our new Fowler syndrome models therefore define the pathobiology of this disease, and provide new insights into brain angiogenesis by showing uncoupling of vessel morphogenesis and blood-brain barrier formation.
Nicolas Santander, Carlos Omar Lizama, Eman Meky, Gabriel L. McKinsey, Bongnam Jung, Dean Sheppard, Christer Betsholtz, Thomas D. Arnold
The microbiome provides resistance to infection. However, mechanisms for this are poorly understood. Here we demonstrate in a murine model that colonization with the intestinal bacterium Clostridium scindens provided protection from Entamoeba histolytica colitis via innate immunity. Introduction of C. scindens into the gut microbiota epigenetically altered and expanded bone marrow granulocyte-monocyte-progenitors (GMPs) and resulted in increased intestinal neutrophils with subsequent challenge with E. histolytica. Introduction of C. scindens alone was sufficient to expand GMPs in gnotobiotic mice. Adoptive transfer of bone-marrow from C. scindens colonized-mice into naïve-mice protected against amebic colitis and increased intestinal neutrophils. Children without E. histolytica diarrhea also had a higher abundance of Lachnoclostridia. Because of the known ability of the Lachnoclostridia C. scindens to metabolize the bile salt cholate, we measured deoxycholate and discovered that it was increased in the sera of C. scindens colonized specific pathogen free and gnotobiotic mice, as well as in children protected from amebiasis. Administration of deoxycholate alone (in the absence of C. scindens) increased GMPs and provided protection from amebiasis. We have discovered a mechanism by which C. scindens and the microbially-metabolized bile salt deoxycholic acid alter hematopoietic precursors and provide innate protection from later infection with Entamoeba histolytica.
Stacey L. Burgess, Jhansi L. Leslie, Md. Jashim Uddin, David Noah Oakland, Carol A. Gilchrist, G. Brett Moreau, Koji Watanabe, Mahmoud M. Saleh, Morgan Simpson, Brandon A. Thompson, David T. Auble, Stephen D. Turner, Natasa Giallourou, Jonathan Swann, Zhen Pu, Jennie Z. Ma, Rashidul Haque, William A. Petri, Jr.
Hepatocellular carcinoma (HCC) is difficult to detect, carries a poor prognosis, and is one of few cancers with an increasing yearly incidence. Molecular defects in complement factor H (CFH), a critical regulatory protein of the complement alternative pathway (AP), are typically associated with inflammatory diseases of the eye and kidney. Little is known regarding the role of CFH in controlling complement activation with the liver. While studying aging CFH-deficient (fH–/–) mice, we observed spontaneous hepatic tumor formation in more than 50% of aged fH–/– males. Examination of fH–/– livers (3–24 months) for evidence of complement-mediated inflammation revealed widespread deposition of complement activation fragments throughout the sinusoids, elevated transminase levels, increased hepatic CD8+ and F4/80+ cells, overexpress of hepatic mRNA associated with inflammatory signaling pathways, steatosis and increased collagen deposition. Immunostaining of human HCC biopsies revealed extensive deposition of complement fragments within the tumors. Interrogation of the Cancer Genome Atlas also revealed that increased CFH mRNA expression is associated with improved survival in HCC patients, whereas mutations are associated with worse survival. These results indicate that CFH is critical for controlling complement activation in the liver, and in its absence, AP activation leads to chronic inflammation and promotes hepatic carcinogenesis.
Jennifer Laskowski, Brandon Renner, Matthew C. Pickering, Natalie J. Serkova, Peter M. Smith-Jones, Eric T. Clambey, Raphael A. Nemenoff, Joshua M. Thurman
There are more than 7000 described rare diseases, most lacking specific treatment. Autosomal-dominant hyper-IgE syndrome (AD-HIES, Job’s syndrome) is caused by mutations in signal transducer and activator of transcription 3 (STAT3). These patients present with immunodeficiency accompanied by severe non-immunological features including skeletal, connective tissue and vascular abnormalities, poor post-infection lung healing, and subsequent pulmonary failure. No specific therapies are available for these abnormalities. Here we investigated underlying mechanisms in order to identify therapeutic targets. Histological analysis of skin wounds demonstrated delayed granulation tissue formation and vascularization during skin wound healing in AD-HIES patients. Global gene expression analysis in AD-HIES patient skin fibroblasts identified deficiencies in a STAT3 controlled transcriptional network regulating extracellular matrix (ECM) remodeling and angiogenesis, with hypoxia inducible factor 1α (HIF1α) being a major contributor. Consistent with this, histological analysis of skin wounds and coronary arteries from AD-HIES patients showed decreased HIF1α expression, and revealed abnormal organization of the ECM and altered formation of the coronary vasa vasorum. Disease modeling utilizing cell culture and mouse models of angiogenesis and wound healing confirmed these predicted deficiencies and demonstrated therapeutic benefit of HIF1α stabilizing drugs. The study provides mechanistic insights into AD-HIES pathophysiology and finds new treatment option for this rare disease.
Natalia I. Dmitrieva, Avram D. Walts, Dai P. Nguyen, Alex Grubb, Xue Zhang, Xujing Wang, Xianfeng Ping, Hui Jin, Zhen Yu, Zu-Xi Yu, Dan Yang, Robin Schwartzbeck, Clifton L. Dalgard, Beth A. Kozel, Mark D. Levin, Russell H. Knutsen, Delong Liu, Joshua D. Milner, Diego B. López, Michael P. O'Connell, Chyi-Chia R. Lee, Ian A. Myles, Amy P. Hsu, Alexandra F. Freeman, Steven M. Holland, Guibin Chen, Manfred Boehm
Molecular mechanisms governing the development of mammalian cochlea, the hearing organ, remain largely unknown. Through genome sequencing in three subjects from two families with non-syndromic cochlear aplasia, we identified homozygous 221 KB and 338 KB deletions in a non-coding region on chromosome 8 with an ~200 KB overlapping section. Genomic location of the overlapping deleted region was starting from ~350 KB downstream of GDF6. Otic lineage cells differentiated from induced pluripotent stem cells derived from an affected individual show reduced expression of GDF6 compared to control cells. A mouse knock-out of Gdf6 reveals cochlear aplasia closely resembling the human phenotype. We conclude that GDF6 plays a necessary role in early cochlear development controlled by cis-regulatory elements located within ~500 KB region of the genome in humans and that its disruption leads to deafness due to cochlear aplasia.
Guney Bademci, Clemer Abad, Filiz Basak Cengiz, Serhat Seyhan, Armagan Incesulu, Shengru Guo, Suat Fitoz, Emine Ikbal Atli, Nicholas C. Gosstola, Selma Demir, Brett M. Colbert, Gozde Cosar Seyhan, Claire J. Sineni, Duygu Duman, Hakan Gurkan, Cynthia Casson Morton, Derek M. Dykxhoorn, Katherina Walz, Mustafa Tekin
Retinitis pigmentosa (RP) is a genetically heterogenous group of eye diseases in which initial degeneration of rods triggers secondary degeneration of cones, leading to significant loss of daylight, color, and high-acuity vision. Gene complementation with adeno-associated viral (AAV) vectors is one strategy to treat RP. Its implementation faces substantial challenges, however — e.g., the tremendous number of loci with causal mutations. Gene therapy targeting secondary cone degeneration is an alternative approach that could provide a much-needed generic treatment for many RP patients. Here, we show that microglia are required for the upregulation of potentially neurotoxic inflammatory factors during cone degeneration in RP, creating conditions that might contribute to cone dysfunction and death. To ameliorate the effects of such factors, we used AAV vectors to express isoforms of the anti-inflammatory cytokine transforming growth factor-beta (TGF-β). AAV-mediated delivery of TGF-β1 rescued degenerating cones in three mouse models of RP carrying different pathogenic mutations. Treatment with TGF-β1 protected vision, as measured by two behavioral assays, and could be pharmacologically disrupted by either depleting microglia or blocking the TGF-β receptors. Our results suggest that TGF-β1 may be broadly beneficial for patients with cone degeneration, and potentially other forms of neurodegeneration, through a pathway dependent upon microglia.
Sean K. Wang, Yunlu Xue, Constance L. Cepko
Medications that target catecholamine-associated inflammation may prevent cytokine storm syndrome associated with COVID-19 and other diseases.
Maximilian F. Konig, Michael A. Powell, Verena Staedtke, Ren-Yuan Bai, David L. Thomas, Nicole M. Fischer, Sakibul Huq, Adham M. Khalafallah, Allison Koenecke, Ruoxuan Xiong, Brett Mensh, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Joshua T. Vogelstein, Susan Athey, Shibin Zhou, Chetan Bettegowda
Improved pandemic preparedness could be achieved by proactively managing emerging virus threats using available technologies.
Barney S. Graham, Kizzmekia S. Corbett
Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults. Vascular pericyte degeneration is the predominant clinical manifestation of DR, yet the mechanism governing pericyte degeneration is poorly understood. Circular RNAs (circRNAs) play important roles in multiple biological processes and disease progression. Here, we investigated the role of circRNA in pericyte biology and diabetes-induced retinal vascular dysfunction. cZNF532 expression was upregulated in pericytes under diabetic stress, in the retinal vessels of a diabetic murine model, and in the vitreous humor of diabetic patients. cZNF532 silencing reduced the viability, proliferation, and differentiation of pericytes and suppressed the recruitment of pericytes toward endothelial cells in vitro. cZNF532 regulated pericyte biology by acting as a miR-29a-3p sponge and inducing increased expression of NG2, LOXL2, and CDK2. Knockdown of cZNF532 or overexpression of miR-29a-3p aggravated streptozotocin-induced retinal pericyte degeneration and vascular dysfunction. By contrast, overexpression of cZNF532 or inhibition of miR-29a-3p ameliorated human diabetic vitreous-induced retinal pericyte degeneration and vascular dysfunction. Collectively, these data identify a circRNA-mediated mechanism that coordinates pericyte biology and vascular homeostasis in DR. Induction of cZNF532 or antagonism of miR-29a-3p is an exploitable therapeutic approach for the treatment of DR.
Qin Jiang, Chang Liu, Chaopeng Li, Shanshan Xu, Mudi Yao, Huimin Ge, Yanan Sun, Xiumiao Li, Shujie Zhang, Kun Shan, Baihui Liu, Jin Yao, Chen Zhao, Biao Yan
Transcriptional dysregulation is a hallmark of prostate cancer (PCa). We mapped the RNA Polymerase II (RNA Pol II) associated chromatin interactions in normal prostate cells and PCa cells. We discovered thousands of enhancer-promoter, enhancer-enhancer, as well as promoter-promoter chromatin interactions. These transcriptional hubs operate within the framework set by structural proteins—CTCF and cohesins, and are regulated by the cooperative action of master transcription factors, such as the Androgen Receptor (AR) and FOXA1. By combining analyses from metastatic castration resistant PCa (mCRPC) specimens, we show that AR locus amplification contributes to the transcriptional up-regulation of AR gene by increasing the total number of chromatin interaction modules comprising of the AR gene and its distal enhancer. We deconvoluted the transcription control modules of several PCa genes, notably, the biomarker KLK3, lineage-restricted genes (KRT8, KRT18, HOXB13, FOXA1, ZBTB16), the drug target EZH2, and the oncogene MYC. By integrating clinical PCa data, we defined a novel germline-somatic interplay between the PCa risk allele rs684232 and the somatically acquired TMPRSS2-ERG gene fusion in the transcriptional regulation of multiple target genes—VPS53, FAM57A and GEMIN4. Our studies implicate changes in genome organization as a critical determinant of aberrant transcriptional regulation in PCa.
Susmita G. Ramanand, Yong Chen, Jiapei Yuan, Kelly Daescu, Maryou Lambros, Kathleen E. Houlahan, Suzanne Carreira, Wei Yuan, GuemHee Baek, Adam Sharp, Alec Paschalis, Mohammed Kanchwala, Yunpeng Gao, Adam Aslam, Nida Safdar, Xiaowei Zhan, Ganesh V. Raj, Chao Xing, Paul C. Boutros, Johann de Bono, Michael Q. Zhang, Ram S. Mani
Lessons from the Ebola outbreak shows that it is possible to develop rapid and effective clinical research responses without relying on anecdote.
Arthur L. Caplan, Ross Upshur
Myeloid cells comprise a major component of the tumor-microenvironment (TME) promoting tumor growth and immune evasion. By employing a novel small molecule inhibitor of glutamine metabolism, not only were we able to inhibit tumor growth, but we markedly inhibited the generation and recruitment of myeloid-derived suppressor cells (MDSCs). Targeting tumor glutamine metabolism led to a decrease in CSF3 and hence recruitment of MDSCs as well immunogenic cell death leading to an increase in inflammatory tumor-associated macrophages (TAMs). Alternatively, inhibiting glutamine metabolism of the MDSCs themselves led to activation induced cell death and conversion of MDSCs to inflammatory macrophages. Surprisingly, blocking glutamine metabolism also inhibited IDO expression of both the tumor and myeloid derived cells leading to a marked decrease in kynurenine levels. This in turn inhibited the development of metastasis and further enhanced anti-tumor immunity. Indeed, targeting glutamine metabolism rendered checkpoint blockade-resistant tumors susceptible to immunotherapy. Overall, our studies define an intimate interplay between the unique metabolism of tumors and the metabolism of suppressive immune cells.
Min-Hee Oh, Im-Hong Sun, Liang Zhao, Robert D. Leone, Im-Meng Sun, Wei Xu, Samuel L. Collins, Ada J. Tam, Richard L. Blosser, Chirag H. Patel, Judson M. Englert, Matthew L. Arwood, Jiayu Wen, Yee Chan-Li, Lukáš Tenora, Pavel Majer, Rana Rais, Barbara S. Slusher, Maureen R. Horton, Jonathan D. Powell
The Warburg effect is a tumor related phenomenon that may be targeted therapeutically. Here, we showed that glioblastoma cultures and patient tumors harbored super-enhancers in several genes related to the Warburg effect. By conducting a transcriptome analysis followed by chromatin immunoprecipitation (CHIP) sequencing coupled with a comprehensive metabolite analysis in GBM models, we unraveled that FDA-approved global (panobinostat, vorinostat) and selective (romidepsin) histone-deacetylase (HDAC) inhibitors elicited metabolic reprogramming in concert with disruption of several Warburg-effect related super-enhancers. Extracellular flux and carbon tracing analyses revealed that HDAC inhibitors blunted glycolysis in a c-Myc dependent manner accompanied by lower ATP levels. This resulted in engagement of oxidative phosphorylation (OXPHOS) driven by elevated fatty acid oxidation (FAO), rendering GBM cells dependent on these pathways. Mechanistically, interference with HDAC1/2 elicited a suppression of c-Myc protein levels and a concomitant increase of two transcriptional drivers of oxidative metabolism, PGC1A and PPARD, suggesting an inverse relationship. Rescue and CHIP experiments indicated that c-Myc bound to the promoter regions of PGC1A and PPARD to counteract their up-regulation driven by HDAC1/2 inhibition. Finally, we demonstrated that the combination treatment of HDAC and FAO inhibitors extended animal survival in patient-derived xenograft (PDX) model systems in vivo more potently than single treatments in the absence of toxicity.
Trang Nguyen, Yiru Zhang, Enyuan Shang, Chang Shu, Consuelo Torrini, Junfei Zhao, Elena Bianchetti, Angeliki Mela, Nelson Humala, Aayushi Mahajan, Arif O. Harmanci, Zhengdeng Lei, Mark Maienschein-Cline, Catarina Maria Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Jeffrey N. Bruce, Peter Canoll, Markus D. Siegelin
Backgroun NK cells are activated by innate cytokines and viral ligands to kill virus-infected cells; these functions are enhanced during secondary immune responses and after vaccination by synergy with effector T cells and virus-specific antibodies. In human Ebola virus infection, clinical outcome is strongly associated with the initial innate cytokine response, but the role of NK cells has not been thoroughly examined. Methods The novel 2-dose heterologous Adenovirus type 26.ZEBOV (Ad26.ZEBOV) and modified vaccinia Ankara-BN-Filo (MVA-BN-Filo) vaccine regimen is safe and provides specific immunity against Ebola glycoprotein, and is currently in phase 2 and 3 studies. Here, we analysed NK cell phenotype and function in response to Ad26.ZEBOV, MVA-BN-Filo vaccination regimen, and in response to in vitro Ebola glycoprotein stimulation of PBMC isolated before and after vaccination. Results We show enhanced NK cell proliferation and activation after vaccination compared with baseline. Ebola glycoprotein-induced activation of NK cells was dependent on accessory cells and TLR-4-dependent innate cytokine secretion (predominantly from CD14+ monocytes) and enriched within less differentiated NK cell subsets. Optimal NK cell responses were dependent on IL-18 and IL-12, whilst IFN-γ secretion was restricted by high concentrations of IL-10. Conclusion This study demonstrates the induction of NK cell effector functions early after Ad26.ZEBOV, MVA-BN-Filo vaccination and provides a mechanism for the activation and regulation of NK cells by Ebola GP. Trial registration ClinicalTrials.gov Identifier: NCT02313077 Funding U.K. Medical Research Council Studentship in Vaccine Research, Innovative Medicines Initiative 2 Joint Undertaking, EBOVAC (Grant 115861) and Crucell Holland (now Janssen Vaccines & Prevention B.V.), European Union’s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations (EFPIA).
Helen R. Wagstaffe, Elizabeth A. Clutterbuck, Viki Bockstal, Jeroen N. Stoop, Kerstin Luhn, Macaya J. Douoguih, Georgi Shukarev, Matthew D. Snape, Andrew J. Pollard, Eleanor M. Riley, Martin Goodier
Background. Given the heightened tolerance to self-starvation in anorexia nervosa, a hypothalamic dysregulation of energy and glucose homeostasis has been hypothesized. Therefore, we investigated whether hypothalamic reactivity to glucose metabolism is impaired in AN. Methods. Twenty-four participants with AN, 28 normal-weight and 24 healthy participants with obesity underwent 2 magnetic resonance imaging (MRI) sessions in a single-blind, random-order, case-controlled crossover design. We used an intragastric infusion of glucose and water to bypass the cephalic phase of food intake. The responsivity of the hypothalamus and the crosstalk of the hypothalamus with reward-related brain regions were investigated using high-resolution MRI. Results. Normal-weight control participants displayed the expected glucose-induced deactivation of hypothalamic activation, whereas patients with AN and participants with obesity showed blunted hypothalamic reactivity. Compared to normal-weight and obese controls, patients with AN failed to show functional connectivity between the hypothalamus and reward-related brain regions during water relative to glucose. Finally, patients with AN displayed typical baseline levels of peripheral appetite hormones during a negative energy balance. Conclusion. These results indicate that blunted hypothalamic glucose reactivity might be related to the pathophysiology of AN. This provides new insights for future research, as it is an extended perspective of the traditional primary nonhomeostatic understanding of the disease. Funding. This study was supported by a grant from the DFG (SI 2087/2-1).
Joe J. Simon, Marion A. Stopyra, Esther Mönning, Sebastian C. A. M. Sailer, Nora Lavandier, Lars Kihm, Martin Bendszus, Hubert Preissl, Wolfgang Herzog, Hans-Christoph Friederich
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 tumours (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 tumour growth, and strongly supressed 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/beta-Catenin, YAP/TAZ, Rb-E2F and BET proteins, 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.
Marta Palomo-Irigoyen, Encarnación Pérez-Andrés, Marta Iruarrizaga-Lejarreta, Adrián Barreira Manrique, Miguel Tamayo-Caro, Laura Vila-Vecilla, Leire Moreno-Cugnon, Nagore Beitia Telletxea, Daniela Medrano, David Fernández-Ramos, Juan-Jose Lozano, Satoshi Okawa, José Luis Lavín, Natalia Martin-Martin, James D. Sutherland, Virginia Gutiérrez-de Juan, Monika Gonzalez-Lopez, Nuria Macias-Camara, David Mosén-Ansorena, Liyam Laraba, C. Oliver Hanemann, Emanuela Ercolano, David B. Parkinson, Christopher W. Schultz, Marcos J. Araúzo-Bravo, Alex M. Ascensión, Daniela Gerovska, Haizea Iribar, Ander Izeta, Peter Pytel, Philipp Krastel, Alessandro Provenzani, Pierfausto Seneci, Ruben D. Carrasco, Antonio del Sol, Maria L. Martinez Chantar, Rosa Barrio, Eduard Serra, Conxi Lázaro, Adrienne M. Flanagan, Myriam Gorospe, Nancy Ratner, Arkaitz Carracedo, Ana María Aransay, Marta Varela-Rey, Ashwin Woodhoo