Musashi proteins are post-transcriptional regulators of the epithelial-luminal cell state

The conserved Musashi (Msi) family of RNA binding proteins are expressed in stem/progenitor and cancer cells, but generally absent from differentiated cells, consistent with a role in cell state regulation. We found that Msi genes are rarely mutated but frequently overexpressed in human cancers and are associated with an epithelial-luminal cell state. Using ribosome profiling and RNA-seq analysis, we found that Msi proteins regulate translation of genes implicated in epithelial cell biology and epithelial-to-mesenchymal transition (EMT), and promote an epithelial splicing pattern. Overexpression of Msi proteins inhibited the translation of Jagged1, a factor required for EMT, and repressed EMT in cell culture and in mammary gland in vivo. Knockdown of Msis in epithelial cancer cells promoted loss of epithelial identity. Our results show that mammalian Msi proteins contribute to an epithelial gene expression program in neural and mammary cell types.National Institutes of Health (U.S.) (Grant RO1-CA084198)National Institutes of Health (U.S.) (Grant U01-CA184897)National Institutes of Health (U.S.) (Grant R01-GM085319)National Science Foundation (U.S.). Graduate Research Fellowship (Grant 1122374

A Pan-cancer analysis reveals high-frequency genetic alterations in mediators of signaling by the tgf-β superfamily

We present an integromic analysis of gene alterations that modulate transforming growth factor β (TGF-β)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA). Focusing on genes that encode mediators and regulators of TGF-β signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers. We identified mutation hotspots in genes that encode TGF-β ligands (BMP5), receptors (TGFBR2, AVCR2A, and BMPR2), and Smads (SMAD2 and SMAD4). Alterations in the TGF-β superfamily correlated positively with expression of metastasis-associated genes and with decreased survival. Correlation analyses showed the contributions of mutation, amplification, deletion, DNA methylation, and miRNA expression to transcriptional activity of TGF-β signaling in each cancer type. This study provides a broad molecular perspective relevant for future functional and therapeutic studies of the diverse cancer pathways mediated by the TGF-β superfamily

Candidate biomarkers from the integration of methylation and gene expression in discordant autistic sibling pairs

While the genetics of autism spectrum disorders (ASD) has been intensively studied, resulting in the identification of over 100 putative risk genes, the epigenetics of ASD has received less attention, and results have been inconsistent across studies. We aimed to investigate the contribution of DNA methylation (DNAm) to the risk of ASD and identify candidate biomarkers arising from the interaction of epigenetic mechanisms with genotype, gene expression, and cellular proportions. We performed DNAm differential analysis using whole blood samples from 75 discordant sibling pairs of the Italian Autism Network collection and estimated their cellular composition. We studied the correlation between DNAm and gene expression accounting for the potential effects of different genotypes on DNAm. We showed that the proportion of NK cells was significantly reduced in ASD siblings suggesting an imbalance in their immune system. We identified differentially methylated regions (DMRs) involved in neurogenesis and synaptic organization. Among candidate loci for ASD, we detected a DMR mapping to CLEC11A (neighboring SHANK1) where DNAm and gene expression were significantly and negatively correlated, independently from genotype effects. As reported in previous studies, we confirmed the involvement of immune functions in the pathophysiology of ASD. Notwithstanding the complexity of the disorder, suitable biomarkers such as CLEC11A and its neighbor SHANK1 can be discovered using integrative analyses even with peripheral tissues

TGFβ pathway limits dedifferentiation following WNT and MAPK pathway activation to suppress intestinal tumourigenesis

Recent studies have suggested increased plasticity of differentiated cells within the intestine to act both as intestinal stem cells (ISCs) and tumour-initiating cells. However, little is known of the processes that regulate this plasticity. Our previous work has shown that activating mutations of Kras or the NF-κB pathway can drive dedifferentiation of intestinal cells lacking Apc. To investigate this process further, we profiled both cells undergoing dedifferentiation in vitro and tumours generated from these cells in vivo by gene expression analysis. Remarkably, no clear differences were observed in the tumours; however, during dedifferentiation in vitro we found a marked upregulation of TGFβ signalling, a pathway commonly mutated in colorectal cancer (CRC). Genetic inactivation of TGFβ type 1 receptor (Tgfbr1/Alk5) enhanced the ability of KrasG12D/+ mutation to drive dedifferentiation and markedly accelerated tumourigenesis. Mechanistically this is associated with a marked activation of MAPK signalling. Tumourigenesis from differentiated compartments is potently inhibited by MEK inhibition. Taken together, we show that tumours arising in differentiated compartments will be exposed to different suppressive signals, for example, TGFβ and blockade of these makes tumourigenesis more efficient from this compartment

The molecular and cellular origin of human prostate cancer

Prostate cancer is the most commonly diagnosed male malignancy. Despite compelling epidemiology, there are no definitive aetiological clues linking development to frequency. Pre-malignancies such as proliferative inflammatory atrophy (PIA) and prostatic intraepithelial neoplasia (PIN) yield insights into the initiating events of prostate cancer, as they supply a background "field" for further transformation. An inflammatory aetiology, linked to recurrent prostatitis, and heterologous signalling from reactive stroma and infiltrating immune cells may result in cytokine addiction of cancer cells, including a tumour-initiating population also known as cancer stem cells (CSCs). In prostate tumours, the background mutational rate is rarely exceeded, but genetic change via profound sporadic chromosomal rearrangements results in copy number variations and aberrant gene expression. In cancer, dysfunctional differentiation is imposed upon the normal epithelial lineage, with disruption/disappearance of the basement membrane, loss of the contiguous basal cell layer and expansion of the luminal population. An initiating role for androgen receptor (AR) is attractive, due to the luminal phenotype of the tumours, but alternatively a pool of CSCs, which express little or no AR, has also been demonstrated. Indolent and aggressive tumours may also arise from different stem or progenitor cells. Castrate resistant prostate cancer (CRPC) remains the inevitable final stage of disease following treatment. Time-limited effectiveness of second-generation anti-androgens, and the appearance of an AR-neuroendocrine phenotype imply that metastatic disease is reliant upon the plasticity of the CSC population, and indeed CSC gene expression profiles are most closely related to those identified in CRPCs

On the use of ray tracing for performance prediction of UWB indoor localization systems

The most important factors impairing the performance of radio-based indoor localization systems are propagation effects like strong reflections or diffuse scattering. To the full extent, these effects can be captured only by time-consuming measurement campaigns. Ray tracing (RT) offers the possibility to predict the radio channel for a certain environment, avoiding the need for measurements. However, it is crucial to include all relevant propagation mechanisms in the RT as well as to validate the obtained results. In this paper, we show that sub-band divided RT can yield realistic ultra-wideband channel impulse responses that can be used instead of real measurements. We show this by using the RT results for performance prediction of multipathassisted localization, which depends to a great extent on the above mentioned propagation effects. A previously introduced method to estimate the ratio of the signal energies of deterministically reflected paths to diffuse scattered components is employed on both the RT results and the channel measurements in an indoor environment. This analysis is useful in two ways: first, as this ratio scales the amount of position-related information of deterministic multipath components, it can be used for localization performance prediction; second, this ratio includes two main propagation mechanisms and is thus useful to validate the subband divided RT

Genetic diversity and drug susceptibility profile of Mycobacterium tuberculosis isolated from different regions of India

International audienceObjectives:Molecular genotyping profiles of Mycobacterium tuberculosis (MTB) provide a valuable insight into the evolution and transmission of the bacilli. Due to the lack of comprehensive national level data from India on this subject, we performed this study to determine the recent trends and distribution of various MTB lineages circulating in India.Methods:A total of 628 MTB isolates were obtained from North, West, South, Central and Eastern India. Spoligotyping and drug susceptibility testing was performed by using manufacturer's instructions.Results:Spoligotyping detected 102 distinct spoligo-patterns. A total of 536 (85.3%) isolates were distributed into 85 SITs which matched the pre-existing database, whereas 17 SITs were newly created for 34 (5.4%) isolates. Overall, CAS family genotype was predominant, comprising 222 (35.4%) isolates, followed by EAI in 152 (24.2%), Beijing in 108 (17.2%), Manu in 41 (6.5%), T in 30 (4.8%), H in 6 (0.9%), X in 3 (0.5%) and one (0.2%) each in Ural and AFRI. Drug susceptibility testing identified 134 (21.3%) isolates as multi drug resistant (MDR).Conclusions:The CAS lineage had a pan India presence but EAI lineage was confined to southern parts of India. Beijing genotype of MTB was significantly associated (p-value <0.0001) with MDR