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The androgen receptor (AR) is a key regulator of prostate growth and the principal drug target for the treatment of prostate cancer. Previous studies have mapped AR targets and identified some candidates which may contribute to cancer progression, but did not characterize AR biology in an integrated manner. In this study, we took an interdisciplinary approach, integrating detailed genomic studies with metabolomic profiling and identify an anabolic transcriptional network involving AR as the core regulator. Restricting flux through anabolic pathways is an attractive approach to deprive tumours of the building blocks needed to sustain tumour growth. Therefore, we searched for targets of the AR that may contribute to these anabolic processes and could be amenable to therapeutic intervention by virtue of differential expression in prostate tumours. This highlighted calcium/calmodulin‐dependent protein kinase kinase 2, which we show is overexpressed in prostate cancer and regulates cancer cell growth via its unexpected role as a hormone‐dependent modulator of anabolic metabolism. In conclusion, it is possible to progress from transcriptional studies to a promising therapeutic target by taking an unbiased interdisciplinary approach. Using a combination of genomic and metabolomic profiling strategies, the CAMKK2 kinase is identified as a critical downstream target of the androgen receptor. CAMKK2 regulates anabolic flux, and represents an attractive therapeutic target for prostate cancer treatments.

Fibrotic remodeling is the primary driver of functional loss in chronic kidney disease, with no specific anti-fibrotic agent available for clinical use. Transglutaminase 2 (TG2), a wound response enzyme that irreversibly crosslinks extracellular matrix proteins causing dysregulation of extracellular matrix turnover, is a well-characterized anti-fibrotic target in the kidney. We describe the humanization and characterization of two anti-TG2 monoclonal antibodies (zampilimab [hDC1/UCB7858] and BB7) that inhibit crosslinking by TG2 in human in vitro and rabbit/cynomolgus monkey i n vivo models of chronic kidney disease. Determination of zampilimab half-maximal inhibitory concentration (IC 50 ) against recombinant human TG2 was undertaken using the KxD assay and determination of dissociation constant (K d ) by surface plasmon resonance. Efficacy in vitro was established using a primary human renal epithelial cell model of tubulointerstitial fibrosis, to assess mature deposited extracellular matrix proteins. Proof of concept in vivo used a cynomolgus monkey unilateral ureteral obstruction model of chronic kidney disease. Zampilimab inhibited TG2 crosslinking transamidation activity with an IC 50 of 0.25 nM and K d of <50 pM. In cell culture, zampilimab inhibited extracellular TG2 activity (IC 50 119 nM) and dramatically reduced transforming growth factor-β1-driven accumulation of multiple extracellular matrix proteins including collagens I, III, IV, V, and fibronectin. Intravenous administration of BB7 in rabbits resulted in a 68% reduction in fibrotic index at Day 25 post-unilateral ureteral obstruction. Weekly intravenous administration of zampilimab in cynomolgus monkeys with unilateral ureteral obstruction reduced fibrosis at 4 weeks by >50%, with no safety signals. Our data support the clinical investigation of zampilimab for the treatment of kidney fibrosis.

Activated fibroblasts are considered major drivers of fibrotic disease progression through the production of excessive extracellular matrix (ECM) in response to signals from damaged epithelial and inflammatory cells. Nevertheless, epithelial cells are capable of expressing components of the ECM, cross-linking enzymes that increase its stability and are sensitive to factors involved in the early stages of fibrosis. We therefore wanted to test the hypothesis that epithelial cells can deposit ECM in response to stimulation in a comparable manner to fibroblasts. We performed immunofluorescence analysis of components of stable, mature extracellular matrix produced by primary human renal proximal tubular epithelial cells and renal fibroblasts in response to cytokine stimulation. Whilst fibroblasts produced a higher basal level of extracellular matrix components, epithelial cells were able to deposit significant levels of fibronectin, collagen I, III and IV in response to cytokine stimulation. In response to hypoxia, epithelial cells showed an increase in collagen IV deposition but not in response to the acute stress stimuli aristolochic acid or hydrogen peroxide. When epithelial cells were in co-culture with fibroblasts we observed significant increases in the level of matrix deposition which could be reduced by transforming growth factor beta (TGF-β) blockade. Our results highlight the role of epithelial cells acting as efficient producers of stable extracellular matrix which could contribute to renal tubule thickening in fibrosis.

Castrate‐resistant prostate cancer (CRPC) is poorly characterized and heterogeneous and while the androgen receptor (AR) is of singular importance, other factors such as c‐Myc and the E2F family also play a role in later stage disease. HES6 is a transcription co‐factor associated with stem cell characteristics in neural tissue. Here we show that HES6 is up‐regulated in aggressive human prostate cancer and drives castration‐resistant tumour growth in the absence of ligand binding by enhancing the transcriptional activity of the AR, which is preferentially directed to a regulatory network enriched for transcription factors such as E2F1. In the clinical setting, we have uncovered a HES6‐associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted by inhibition of PLK1 with restoration of sensitivity to castration. We have therefore shown for the first time the critical role of HES6 in the development of CRPC and identified its potential in patient‐specific therapeutic strategies. Synopsis HES6 promotes castration resistance, maintains AR chromatin binding at a subset of sites in the absence of hormone stimulation and predicts poor outcome after prostatectomy. Inhibition of HES6‐responsive gene PLK1 enhances anti‐androgen sensitivity. HES6 promotes castration resistance in prostate cancer cells. HES6 maintains AR chromatin binding at a subset of sites in the absence of hormone stimulation. HES6‐associated genes predict poor clinical outcome after radical prostatectomy. HES6‐responsive gene PLK1 is highly expressed in a new hormone relapse TMA. Inhibition of PLK1 enhances sensitivity to anti‐androgens. Graphical Abstract HES6 promotes castration resistance, maintains AR chromatin binding at a subset of sites in the absence of hormone stimulation and predicts poor outcome after prostatectomy. Inhibition of HES6‐responsive gene PLK1 enhances anti‐androgen sensitivity.

Fibrosis is a common driver of end-stage organ failure in most organs. It is characterised by excessive accumulation of extracellular matrix (ECM) proteins. Therapeutic options are limited and novel treatments are urgently required, however current cell-based high-throughput screening (HTS) models to identify molecules affecting ECM accumulation are limited in their relevance or throughput. We report a novel sensitive approach which combines in situ fluorescent staining of accumulated decellularised ECM proteins with automated high-content microscopy. Using this method to measure ECM accumulation in a kidney cell model, we demonstrated good agreement with established radiolabelled amino acid incorporation assays: TGFβ1 delivered a potent pro-fibrotic stimulus, which was reduced by TGFβ antibody or the anti-fibrotic nintedanib. Importantly, our method also provides information about matrix organisation: the extent of ECM accumulation was unaffected by the BMP antagonist Gremlin-1 but a pronounced effect on matrix fibrillar organisation was revealed. This rapid, straightforward endpoint provides quantitative data on ECM accumulation and offers a convenient cross-species readout that does not require antibodies. Our method facilitates discovery of novel pro- and anti-fibrotic agents in 384-well plate format and may be widely applied to in vitro cell-based models in which matrix protein deposition reflects the underlying biology or pathology.

Castrate‐resistant prostate cancer ( CRPC ) is poorly characterized and heterogeneous and while the androgen receptor ( AR ) is of singular importance, other factors such as c‐Myc and the E2F family also play a role in later stage disease. HES6 is a transcription co‐factor associated with stem cell characteristics in neural tissue. Here we show that HES6 is up‐regulated in aggressive human prostate cancer and drives castration‐resistant tumour growth in the absence of ligand binding by enhancing the transcriptional activity of the AR , which is preferentially directed to a regulatory network enriched for transcription factors such as E 2 F 1. In the clinical setting, we have uncovered a HES6‐associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted by inhibition of PLK1 with restoration of sensitivity to castration. We have therefore shown for the first time the critical role of HES6 in the development of CRPC and identified its potential in patient‐specific therapeutic strategies. image HES6 promotes castration resistance, maintains AR chromatin binding at a subset of sites in the absence of hormone stimulation and predicts poor outcome after prostatectomy. Inhibition of H ES6‐responsive gene PLK 1 enhances anti‐androgen sensitivity. HES6 promotes castration resistance in prostate cancer cells. HES6 maintains AR chromatin binding at a subset of sites in the absence of hormone stimulation. HES6‐associated genes predict poor clinical outcome after radical prostatectomy. HES6‐responsive gene PLK 1 is highly expressed in a new hormone relapse TMA . Inhibition of PLK 1 enhances sensitivity to anti‐androgens.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

Among the many fascinating examples of collective behavior exhibited by animal groups, some species are known to alternate slow group dispersion in space with rapid aggregation phenomena induced by a sudden behavioral shift at the individual level. We study this phenomenon quantitatively in large groups of grazing Merino sheep under controlled experimental conditions. Our analysis reveals strongly intermittent collective dynamics consisting of fast, avalanche-like regrouping events distributed on all experimentally accessible scales. As a proof of principle, we introduce an agent-based model with individual behavioral shifts, which we show to account faithfully for all collective properties observed. This offers, in turn, an insight on the individual stimulus/response functions that can generate such intermittent behavior. In particular, the intensity of sheep allelomimetic behavior plays a key role in the group’s ability to increase the per capita grazing surface while minimizing the time needed to regroup into a tightly packed configuration. We conclude that the emergent behavior reported probably arises from the necessity to balance two conflicting imperatives: (i) the exploration of foraging space by individuals and (ii) the protection from predators offered by being part of large, cohesive groups. We discuss our results in the context of the current debate about criticality in biology.

The remains of 61 individuals buried in the cemetery of Jebel Sahaba (site 117) offer unique and substantial evidence to the emergence of violence in the Nile Valley at the end of the Late Pleistocene. Excavated and assessed in the 1960s, some of the original findings and interpretations are disputed. A full reanalysis of the timing, nature and extent of the violence was conducted through the microscopic characterization of the nature of each osseous lesion, and the reassessment of the archaeological data. Over 100 previously undocumented healed and unhealed lesions were identified on both new and/or previously identified victims, including several embedded lithic artefacts. Most trauma appears to be the result of projectile weapons and new analyses confirm for the first time the repetitive nature of the interpersonal acts of violence. Indeed, a quarter of the skeletons with lesions exhibit both healed and unhealed trauma. We dismiss the hypothesis that Jebel Sahaba reflects a single warfare event, with the new data supporting sporadic and recurrent episodes of inter-personal violence, probably triggered by major climatic and environmental changes. At least 13.4 ka old, Jebel Sahaba is one of the earliest sites displaying interpersonal violence in the world.

Monitoring small groups of sheep in spontaneous evolution in the field, we decipher behavioural rules that sheep follow at the individual scale in order to sustain collective motion. Individuals alternate grazing mode at null speed and moving mode at walking speed, so cohesive motion stems from synchronising when they decide to switch between the two modes. We propose a model for the individual decision making process, based on switching rates between stopped / walking states that depend on behind / ahead locations and states of the others. We parametrize this model from data. Next, we translate this (microscopic) individual-based model into its density-flow (macroscopic) equations counterpart. Numerical solving these equations display a traveling pulse propagating at constant speed even though each individual is at any moment either stopped or walking. Considering the minimal model embedded in these equations, we derive analytically the steady shape of the pulse (sech square). The parameters of the pulse (shape and speed) are expressed as functions of individual parameters. This pulse emerges from the non linear coupling of start/stop individual decisions which compensate exactly for diffusion and promotes a steady ratio of walking / stopped individuals, which in turn determines the traveling speed of the pulse. The system seems to converge to this pulse from any initial condition, and to recover the pulse after perturbation. This gives a high robustness to this coordination mechanism.