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

MOLECULAR CONSEQUENCES OF HIGH TAZ EXPRESSION IN GLIOMAS

Diffuse high grade gliomas are complex and lethal neoplasms of the adult central nervous system that are driven by a range of genetic and epigenetic alterations. Molecular classification of these tumors has identified different transcriptional subtypes, the most notable being Proneural (PN) and Mesenchymal (MES) classes. The most aggressive forms of the disease have a Mesenchymal expression signature, with reported PN-to-MES transition occurring with tumor progression. Master regulatory analysis has identified the transcriptional co-activator TAZ (WWTR1) as a major driver of the MES transition. Overexpression of this single protein in glioma stem cells has been shown to drive a transition from a PN to MES cell state. In this study, we explore in depth the consequences of high TAZ expression in clinical glioma samples. We show that TAZ-high gliomas associate with immune infiltration and extracellular matrix genes, whereas TAZ-low gliomas associate with neuronal development genes. Furthermore, TAZ overexpression causes widespread epigenetic alterations in the cell, with consequent silencing of neuronal differentiation factors and an activation of mesenchymal regulators. Directed differentiation of glioma stem cells towards the post-mitotic neuronal state have been shown to be efficient strategies to battle this disease. By establishing the role of TAZ in suppressing the neuronal state in these cells, we argue that silencing of TAZ and/or its effector molecular complexes through therapeutics is a viable strategy. Given that TAZ has been found to be largely dispensable for normal tissue homeostasis, directed targeting of this protein is an attractive potential avenue in finding a cure for GBM

Salmonella escapes antigen presentation through K63 ubiquitination mediated endosomal proteolysis of MHC II via modulation of endosomal acidification in dendritic cells

CD4(+) T-cell response is vital for successful clearance of Salmonella Typhimurium infection. Efficient antigen presentation is crucial for effective CD4(+) T-cell response. Previous study has reported that Salmonella abrogates antigen presentation capacity of dendritic cells in order to escape host adaptive immune response. In this study, we have elucidated the mechanism of Salmonella-mediated downregulation of the total cellular Major Histocompatibility Complex (MHC) II pool in dendritic cells. Infected dendritic cells show upregulation of E3 ubiquitin ligase, MARCH1 expression and K63-linked ubiquitination of MHC II. Salmonella infection also enhances the internalisation of ubiquitin-tagged MHC II molecules that are subsequently degraded by endosomal proteases. In addition, Salmonella regulates the activation of endosomal proteases by lowering the pH of endosomes. In infected dendritic cells, Salmonella delays NOX2 recruitment to the phagosomes thereby preventing its alkalinisation. NOX2 is a significant part of innate immune response against pathogens as it is responsible for Reactive Oxygen Species (ROS) production. In this study, we have demonstrated how Salmonella evades MHC II-mediated adaptive immune response in dendritic cells through enhanced endosomal proteolysis. To escape host CD4 + T response, Salmonella delays NOX2 recruitment, an innate immune response element to the phagosomes

High-dimensional regression analysis links magnetic resonance imaging features and protein expression and signaling pathway alterations in breast invasive carcinoma

Imaging features derived from MRI scans can be used for not only breast cancer detection and measuring disease extent, but can also determine gene expression and patient outcomes. The relationships between imaging features, gene/protein expression, and response to therapy hold potential to guide personalized medicine. We aim to characterize the relationship between radiologist-annotated tumor phenotypic features (based on MRI) and the underlying biological processes (based on proteomic profiling) in the tumor. Multiple-response regression of the image-derived, radiologist-scored features with reverse-phase protein array expression levels generated association coefficients for each combination of image-feature and protein in the RPPA dataset. Significantly-associated proteins for features were analyzed with Ingenuity Pathway Analysis software. Hierarchical clustering of the results of the pathway analysis determined which features were most strongly correlated with pathway activity and cellular functions. Each of the twenty-nine imaging features was found to have a set of significantly correlated molecules, associated biological functions, and pathways. We interrogated the pathway alterations represented by the protein expression associated with each imaging feature. Our study demonstrates the relationships between biological processes (via proteomic measurements) and MRI features within breast tumors

Subclonal evolution and expansion of spatially distinct THY1-positive cells is associated with recurrence in glioblastoma

Purpose: Glioblastoma(GBM) is a lethal disease characterized by inevitable recurrence. Here we investigate the molecular pathways mediating resistance, with the goal of identifying novel therapeutic opportunities. Experimental design: We developed a longitudinal in vivo recurrence model utilizing patient-derived explants to produce paired specimens(pre- and post-recurrence) following temozolomide(TMZ) and radiation(IR). These specimens were evaluated for treatment response and to identify gene expression pathways driving treatment resistance. Findings were clinically validated using spatial transcriptomics of human GBMs. Results: These studies reveal in replicate cohorts, a gene expression profile characterized by upregulation of mesenchymal and stem-like genes at recurrence. Analyses of clinical databases revealed significant association of this transcriptional profile with worse overall survival and upregulation at recurrence. Notably, gene expression analyses identified upregulation of TGFβ signaling, and more than one-hundred-fold increase in THY1 levels at recurrence. Furthermore, THY1-positive cells represented <10% of cells in treatment-naïve tumors, compared to 75-96% in recurrent tumors. We then isolated THY1-positive cells from treatment-naïve patient samples and determined that they were inherently resistant to chemoradiation in orthotopic models. Additionally, using image-guided biopsies from treatment-naïve human GBM, we conducted spatial transcriptomic analyses. This revealed rare THY1+ regions characterized by mesenchymal/stem-like gene expression, analogous to our recurrent mouse model, which co-localized with macrophages within the perivascular niche. We then inhibited TGFBRI activity in vivo which decreased mesenchymal/stem-like protein levels, including THY1, and restored sensitivity to TMZ/IR in recurrent tumors. Conclusions: These findings reveal that GBM recurrence may result from tumor repopulation by pre-existing, therapy-resistant, THY1-positive, mesenchymal cells within the perivascular niche

Metabolomic profiles of human glioma inform patient survival

AIMS: Targeting tumor metabolism may improve the outcomes for patients with glioblastoma (GBM). To further preclinical efforts targeting metabolism in GBM, we tested the hypothesis that brain tumors can be stratified into distinct metabolic groups with different patient outcomes. Therefore, to determine if tumor metabolites relate to patient survival, we profiled the metabolomes of human gliomas and correlated metabolic information with clinical data. RESULTS: We found that isocitrate dehydrogenase-wildtype (IDHwt) GBMs are metabolically distinguishable from IDH mutated (IDHmut) astrocytomas and oligodendrogliomas. Survival of patients with IDHmut gliomas was expectedly more favorable than those with IDHwt GBM, and metabolic signatures can stratify IDHwt GBMs subtypes with varying prognoses. Patients whose GBMs were enriched in amino acids had improved survival while those whose tumors were enriched for nucleotides, redox molecules and lipid metabolites fared more poorly. These findings were recapitulated in validation cohorts using both metabolomic and transcriptomic data. INNOVATION: Our results suggest the existence of metabolic subtypes of GBM with differing prognoses and further support the concept that metabolism may drive the aggressiveness of human gliomas. CONCLUSIONS: Our data show that metabolic signatures of human gliomas can inform patient survival. These findings may be used clinically to tailor novel metabolically targeted agents for GBM patients with different metabolic phenotypes

Epigenetically defined therapeutic targeting in H3.3G34R/V high-grade gliomas

High-grade gliomas with arginine or valine substitutions of the histone H3.3 glycine-34 residue (H3.3G34R/V) carry a dismal prognosis, and current treatments, including radiotherapy and chemotherapy, are not curative. Because H3.3G34R/V mutations reprogram epigenetic modifications, we undertook a comprehensive epigenetic approach using ChIP sequencing and ChromHMM computational analysis to define therapeutic dependencies in H3.3G34R/V gliomas. Our analyses revealed a convergence of epigenetic alterations, including (i) activating epigenetic modifications on histone H3 lysine (K) residues such as H3K36 trimethylation (H3K36me3), H3K27 acetylation (H3K27ac), and H3K4 trimethylation (H3K4me3); (ii) DNA promoter hypomethylation; and (iii) redistribution of repressive histone H3K27 trimethylation (H3K27me3) to intergenic regions at the leukemia inhibitory factor (LIF) locus to drive increased LIF abundance and secretion by H3.3G34R/V cells. LIF activated signal transducer and activator of transcription 3 (STAT3) signaling in an autocrine/paracrine manner to promote survival of H3.3G34R/V glioma cells. Moreover, immunohistochemistry and single-cell RNA sequencing from H3.3G34R/V patient tumors revealed high STAT3 protein and RNA expression, respectively, in tumor cells with both inter- and intratumor heterogeneity. We targeted STAT3 using a blood-brain barrier-penetrable small-molecule inhibitor, WP1066, currently in clinical trials for adult gliomas. WP1066 treatment resulted in H3.3G34R/V tumor cell toxicity in vitro and tumor suppression in preclinical mouse models established with KNS42 cells, SJ-HGGx42-c cells, or in utero electroporation techniques. Our studies identify the LIF/STAT3 pathway as a key epigenetically driven and druggable vulnerability in H3.3G34R/V gliomas. This finding could inform development of targeted, combination therapies for these lethal brain tumors.1

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\ua0with 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

A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily

© 2018 Elsevier Inc. 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. To date, there are no studies of the TGF-β superfamily of signaling pathways across multiple cancers. This study represents a key starting point for unraveling the role of this complex superfamily in 33 divergent cancer types from over 9,000 patients