Abstract:
:Metastatic castration-resistant prostate cancer (mCRPC) is a lethal form of treatment-resistant prostate cancer and poses significant therapeutic challenges. Deregulated receptor tyrosine kinase (RTK) signalling mediated by loss of tumour suppressor Sprouty2 (SPRY2) is associated with treatment resistance. Using pre-clinical human and murine mCRPC models, we show that SPRY2 deficiency leads to an androgen self-sufficient form of CRPC Mechanistically, HER2-IL6 signalling axis enhances the expression of androgen biosynthetic enzyme HSD3B1 and increases SRB1-mediated cholesterol uptake in SPRY2-deficient tumours. Systemically, IL6 elevated the levels of circulating cholesterol by inducing host adipose lipolysis and hepatic cholesterol biosynthesis. SPRY2-deficient CRPC is dependent on cholesterol bioavailability and SRB1-mediated tumoral cholesterol uptake for androgen biosynthesis. Importantly, treatment with ITX5061, a clinically safe SRB1 antagonist, decreased treatment resistance. Our results indicate that cholesterol transport blockade may be effective against SPRY2-deficient CRPC.
journal_name
EMBO Mol Medjournal_title
EMBO molecular medicineauthors
Patel R,Fleming J,Mui E,Loveridge C,Repiscak P,Blomme A,Harle V,Salji M,Ahmad I,Teo K,Hamdy FC,Hedley A,van den Broek N,Mackay G,Edwards J,Sansom OJ,Leung HYdoi
10.15252/emmm.201708347subject
Has Abstractpub_date
2018-04-01 00:00:00issue
4eissn
1757-4676issn
1757-4684pii
emmm.201708347journal_volume
10pub_type
杂志文章abstract::While increased VEGF-A has been associated with neovascular age-related macular degeneration (AMD), it is not known whether VEGF-A may also promote other age-related eye diseases. Here, we show that an increase in VEGF-A is sufficient to cause multiple distinct common aging diseases of the eye, including cataracts and...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201505613
更新日期:2016-03-01 00:00:00
abstract::Sterile inflammation underlies many diseases of the cornea including serious chemical burns and the common dry eye syndrome. In search for therapeutic targets for corneal inflammation, we defined the kinetics of neutrophil infiltration in a model of sterile injury to the cornea and identified molecular and cellular me...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.1002/emmm.201200221
更新日期:2012-05-01 00:00:00
abstract::Sequence variations occurring in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) support an essential function of microglia and innate immunity in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. TREM2 matures within the secretory pathway, and its ectod...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201707672
更新日期:2017-10-01 00:00:00
abstract::The combinations of genetic alterations that cooperate with von Hippel-Lindau (VHL) mutation to cause clear cell renal cell carcinoma (ccRCC) remain poorly understood. We show that the TP53 tumour suppressor gene is mutated in approximately 9% of human ccRCCs. Combined deletion of Vhl and Trp53 in primary mouse embryo...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.1002/emmm.201202231
更新日期:2013-06-01 00:00:00
abstract::Although remnant cardiomyocytes (CMs) possess a certain degree of proliferative ability, efficiency is too low for cardiac regeneration after injury. In this study, we identified a distinct stage within the initiation phase of CM reprogramming before the MET process, and microarray analysis revealed the strong up-regu...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201606558
更新日期:2017-02-01 00:00:00
abstract::Cannabis abuse during adolescence confers an increased risk for developing later in life cognitive deficits reminiscent of those observed in schizophrenia, suggesting common pathological mechanisms that remain poorly characterized. In line with previous findings that revealed a role of 5-HT6 receptor-operated mTOR act...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201910605
更新日期:2020-05-08 00:00:00
abstract::Baricitinib is an oral Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis (RA) that was independently predicted, using artificial intelligence (AI) algorithms, to be useful for COVID-19 infection via proposed anti-cytokine effects and as an inhibitor of host cell viral propagation. W...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.202012697
更新日期:2020-08-07 00:00:00
abstract::Shah et al have recently reported the first successful sequencing of the entire genome of a solid tumour (Shah et al, 2009). Philippe Bedard and Christos Sotiriou analyse their findings as well as the challenges of applying the study of cancer genomes to clinical cancer care. ...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.1002/emmm.200900054
更新日期:2010-01-01 00:00:00
abstract::Human respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV), two members of the Pneumoviridae family, account for the majority of severe lower respiratory tract infections worldwide in very young children. They are also a frequent cause of morbidity and mortality in the elderly and immunocompromised adul...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201708078
更新日期:2018-02-01 00:00:00
abstract::Human memory B cells and plasma cells represent a rich source of antibodies that have been selected in response to human pathogens. In the last decade, different methods have been developed to interrogate the human memory repertoire and isolate monoclonal antibodies. I will discuss how a target-agnostic approach based...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201808879
更新日期:2018-03-01 00:00:00
abstract::Alzheimer's disease (AD) is the most common cause of dementia. There are currently no effective treatments that may delay the onset, slow the progression or prevent the disease. Unless such treatments are developed, the number of AD cases is expected to double in the next 30 years. There is overwhelming genetic and bi...
journal_title:EMBO molecular medicine
pub_type: 评论,杂志文章
doi:10.1002/emmm.200900030
更新日期:2009-07-01 00:00:00
abstract::In the normal quiescent vasculature, only 0.01% of endothelial cells (ECs) are proliferating. However, this proportion increases dramatically following the angiogenic switch during tumor growth or wound healing. Recent evidence suggests that this angiogenic switch is accompanied by a metabolic switch. Here, we show th...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.1002/emmm.201303016
更新日期:2014-05-01 00:00:00
abstract::The insulin/insulin-like growth factor-1 signalling (IIS) pathway regulates cellular and organismal metabolism and controls the rate of aging. Gain-of-function mutations in p110α, the principal mammalian IIS-responsive isoform of PI 3-kinase (PI3K), promote cancer. In contrast, loss-of-function mutations in p110α impa...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.1002/emmm.201201953
更新日期:2013-04-01 00:00:00
abstract::Over thousands of years microbes and mammals have co-evolved, resulting in extraordinarily sophisticated molecular mechanisms permitting the organisms to survive together. Mycobacterium tuberculosis is one of the best examples of successful co-evolution, since the bacilli have infected one third of the human populatio...
journal_title:EMBO molecular medicine
pub_type: 杂志文章,评审
doi:10.1002/emmm.200900008
更新日期:2009-04-01 00:00:00
abstract::Phosphodiesterase type 10A (PDE10A) is highly enriched in striatum and is under evaluation as a drug target for several psychiatric/neurodegenerative diseases. Preclinical studies implicate PDE10A in the regulation of energy homeostasis, but the mechanisms remain unclear. By utilizing small-animal PET/MRI and the nove...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201506085
更新日期:2016-07-01 00:00:00
abstract::Mitochondrial (mt) diseases are multisystem disorders due to mutations in nuclear or mtDNA genes. Among the latter, more than 50% are located in transfer RNA (tRNA) genes and are responsible for a wide range of syndromes, for which no effective treatment is available at present. We show that three human mt aminoacyl-t...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.1002/emmm.201303198
更新日期:2014-02-01 00:00:00
abstract::The angiopoietin (Ang)-Tie pathway has been intensely pursued as candidate second-generation anti-angiogenic target. While much of the translational work has focused on the ligand Ang2, the clinical efficacy of Ang2-targeting drugs is limited and failed to improve patient survival. In turn, the orphan receptor Tie1 re...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201911164
更新日期:2020-06-08 00:00:00
abstract::On November 14 last year, the British Guardian published an account from an anonymous whistleblower at Google, accusing the company of misconduct in regard to handling sensitive health data. The whistleblower works for Project Nightingale, an attempt by Google to get into the lucrative US healthcare market, by storing...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.202012053
更新日期:2020-03-06 00:00:00
abstract::Systemic toxicities have severely limited the clinical application of tumor necrosis factor (TNF) as an anticancer agent. Activity-on-Target cytokines (AcTakines) are a novel class of immunocytokines with improved therapeutic index. A TNF-based AcTakine targeted to CD13 enables selective activation of the tumor neovas...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201911223
更新日期:2020-02-07 00:00:00
abstract::Candida albicans is a frequent aetiologic agent of sepsis associated with high mortality in immunocompromised patients. Developing new antifungal therapies is a medical need due to the low efficiency and resistance to current antifungal drugs. Here, we show that p38γ and p38δ regulate the innate immune response to C. ...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201708485
更新日期:2018-05-01 00:00:00
abstract::Senescent cells accumulate in multiple aging-associated diseases, and eliminating these cells has recently emerged as a promising therapeutic approach. Here, we take advantage of the high lysosomal β-galactosidase activity of senescent cells to design a drug delivery system based on the encapsulation of drugs with gal...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201809355
更新日期:2018-09-01 00:00:00
abstract::RAD51 recombinase activity plays a critical role for cancer cell proliferation and survival, and often contributes to drug-resistance. Abnormally elevated RAD51 function and hyperactive homologous recombination (HR) rates have been found in a panel of cancers, including breast cancer and chronic myeloid leukaemia (CML...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.1002/emmm.201201760
更新日期:2013-03-01 00:00:00
abstract::Familial Mediterranean fever (FMF) is the most frequent hereditary systemic autoinflammatory syndrome. FMF is usually caused by biallelic mutations in the MEFV gene, encoding Pyrin. Conclusive genetic evidence lacks for about 30% of patients diagnosed with clinical FMF. Pyrin is an inflammasome sensor maintained inact...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201910547
更新日期:2019-11-07 00:00:00
abstract::Muscle-invasive forms of urothelial carcinomas are responsible for most mortality in bladder cancer. Finding new treatments for invasive bladder tumours requires adequate animal models to decipher the mechanisms of progression, in particular the way tumours interact with their microenvironment. Herein, using the murin...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.1002/emmm.201302655
更新日期:2013-12-01 00:00:00
abstract::Both the incidence and prevalence of inflammatory bowel disease (IBD) is increasing globally; in the industrialized world up to 0.5% of the population are affected and around 4.2 million individuals suffer from IBD in Europe and North America combined. Successful engraftment in experimental colitis models suggests tha...
journal_title:EMBO molecular medicine
pub_type: 杂志文章,评审
doi:10.15252/emmm.201607260
更新日期:2017-05-01 00:00:00
abstract::Genomic data sharing is becoming more important as scientists join forces across borders in biomedical research for the benefit of patients and society. The EU's General Data Protection Regulation (GDPR) helps simplify sharing of such data at the European and international level. However, initial optimism has dried up...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201911421
更新日期:2020-03-06 00:00:00
abstract::Activation of non-shivering thermogenesis (NST) in brown adipose tissue (BAT) has been proposed as an anti-obesity treatment. Moreover, cold-induced glucose uptake could normalize blood glucose levels in insulin-resistant patients. It is therefore important to identify novel regulators of NST and cold-induced glucose ...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201505610
更新日期:2016-03-01 00:00:00
abstract::Mitochondrial metabolism and the generation of reactive oxygen species (ROS) contribute to the acquisition of DNA mutations and genomic instability in cancer. How genomic instability influences the metabolic capacity of cancer cells is nevertheless poorly understood. Here, we show that homologous recombination-defecti...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201911217
更新日期:2020-06-08 00:00:00
abstract::Fibroblast growth factors (FGFs) play key roles in the pathogenesis of different human diseases, but the cross-talk between FGFs and other cytokines remains largely unexplored. We identified an unexpected antagonistic effect of FGFs on the interferon (IFN) signaling pathway. Genetic or pharmacological inhibition of FG...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201911793
更新日期:2020-09-07 00:00:00
abstract::Mitochondrial disorders (MDs) are inherited multi-organ diseases with variable phenotypes. Inclusion body myositis (IBM), a sporadic inflammatory muscle disease, also shows mitochondrial dysfunction. We investigated whether primary and secondary MDs modify metabolism to reveal pathogenic pathways and biomarkers. We in...
journal_title:EMBO molecular medicine
pub_type: 杂志文章
doi:10.15252/emmm.201809091
更新日期:2018-12-01 00:00:00