Resistance to platinum compounds is a major determinant of patient survival in high-grade serous ovarian cancer (HGSOC). To understand mechanisms of platinum resistance and identify potential ...therapeutic targets in resistant HGSOC, we generated a data resource composed of dynamic (±carboplatin) protein, post-translational modification, and RNA sequencing (RNA-seq) profiles from intra-patient cell line pairs derived from 3 HGSOC patients before and after acquiring platinum resistance. These profiles reveal extensive responses to carboplatin that differ between sensitive and resistant cells. Higher fatty acid oxidation (FAO) pathway expression is associated with platinum resistance, and both pharmacologic inhibition and CRISPR knockout of carnitine palmitoyltransferase 1A (CPT1A), which represents a rate limiting step of FAO, sensitize HGSOC cells to platinum. The results are further validated in patient-derived xenograft models, indicating that CPT1A is a candidate therapeutic target to overcome platinum resistance. All multiomic data can be queried via an intuitive gene-query user interface (https://sites.google.com/view/ptrc-cell-line).
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•Multi-omic profiles of platinum-resistant and sensitive ovarian cancer models•Significant alterations in multiomic profiles after carboplatin exposure•Oxidative phosphorylation and fatty acid oxidation (FAO) implicated in resistance•FAO/CPT1A may be a candidate druggable pathway to overcome platinum resistance
Huang et al. report extensive multiomic profiling of preclinical models of high-grade serous ovarian cancer and identify molecular features associated with resistance to standard-of-care, platinum-based chemotherapy. Functional data are presented, demonstrating that CPT1A is a candidate therapeutic target to overcome platinum resistance.
We present new optical emission-line images of the young SNR 1E 0102-7219 in the SMC obtained with the ACS on HST. This object is a member of the oxygen-rich class of SNRs showing strong oxygen, ...neon, and other metal-line emissions in its optical and X-ray spectra, and an absence of hydrogen and helium. The progenitor of 1E 0102-7219 may have been a Wolf-Rayet star that underwent considerable mass loss prior to exploding as a Type Ib/c or IIL/b supernova. The ejecta in this SNR are generally fast-moving (V > 1000 km s super(-1)) and emit as they are compressed and heated in the reverse shock. In 2003 we obtained optical O III, Ha, and continuum images with the ACS Wide Field Camera. The O III image through the F475W filter captures the full velocity range of the ejecta and shows considerable high-velocity emission projected in the middle of the SNR that was Doppler-shifted out of the narrow F502N bandpass of a previous WFPC2 image from 1995. Using these two epochs separated by 68.5 yr, we measure the transverse expansion of the ejecta around the outer rim in this SNR for the first time at visible wavelengths. From proper-motion measurements of 12 ejecta filaments, we estimate a mean expansion velocity for the bright ejecta of 62000 km s super(-1) and an inferred kinematic age for the SNR of 62050 c 600 yr. The age we derive from HST data is about twice that inferred by Hughes et al. from X-ray data, although our 1 s error bars overlap. Our proper-motion age is consistent with an independent optical kinematic age derived by Eriksen et al. in 2003 using spatially resolved O III radial-velocity data. We derive an expansion center that lies very close to conspicuous X-ray and radio hot spots, which could indicate the presence of a compact remnant (neutron star or black hole).
Fluorescence spectroscopy and microscopy imaging are widely used at ambient pressure for analytical studies on biological systems. Before using fluorescence‐based methods at high pressures, ...biochemical and metabolic probes need to be characterized under pressure to ensure valid quantitative results. In this review, we describe the principles behind the use of fluorescent probe dyes for ion sensing and provide models for interpreting the dye spectrum under pressure. We then review results from three studies using the excited‐state emission from probe dyes sensitive to pH and calcium‐ion concentration, demonstrating some ways pressure may affect probe operation.
To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization of 110 tumors and 101 matched normal ...adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, and acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, and gender. Proteomic and phosphoproteomic data illuminated biology downstream of copy number aberrations, somatic mutations, and fusions and identified therapeutic vulnerabilities associated with driver events involving KRAS, EGFR, and ALK. Immune subtyping revealed a complex landscape, reinforced the association of STK11 with immune-cold behavior, and underscored a potential immunosuppressive role of neutrophil degranulation. Smoking-associated LUADs showed correlation with other environmental exposure signatures and a field effect in NATs. Matched NATs allowed identification of differentially expressed proteins with potential diagnostic and therapeutic utility. This proteogenomics dataset represents a unique public resource for researchers and clinicians seeking to better understand and treat lung adenocarcinomas.
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•Comprehensive LUAD proteogenomics exposes multi-omic clusters and immune subtypes•Phosphoproteomics identifies candidate ALK-fusion diagnostic markers and targets•Candidate drug targets: PTPN11 (EGFR), SOS1 (KRAS), neutrophil degranulation (STK11)•Phospho and acetyl modifications denote tumor-specific markers and druggable proteins
Comprehensive proteogenomic characterization of lung adenocarcinomas and paired normal adjacent tissues from patients of diverse smoking status and country of origin yields insights into cancer taxonomy, oncogenesis, and immune response; offers novel candidate biomarkers and therapeutic targets; and provides a community resource for further discovery.
We undertook a comprehensive proteogenomic characterization of 95 prospectively collected endometrial carcinomas, comprising 83 endometrioid and 12 serous tumors. This analysis revealed possible new ...consequences of perturbations to the p53 and Wnt/β-catenin pathways, identified a potential role for circRNAs in the epithelial-mesenchymal transition, and provided new information about proteomic markers of clinical and genomic tumor subgroups, including relationships to known druggable pathways. An extensive genome-wide acetylation survey yielded insights into regulatory mechanisms linking Wnt signaling and histone acetylation. We also characterized aspects of the tumor immune landscape, including immunogenic alterations, neoantigens, common cancer/testis antigens, and the immune microenvironment, all of which can inform immunotherapy decisions. Collectively, our multi-omic analyses provide a valuable resource for researchers and clinicians, identify new molecular associations of potential mechanistic significance in the development of endometrial cancers, and suggest novel approaches for identifying potential therapeutic targets.
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•Proteogenomics provides new insights into oncogenic signaling in endometrial carcinoma•Global acetylome and phosphoproteome surveys identify new regulatory mechanisms•QKI, circRNAs, and miRNAs form a potential feedback loop to promote EMT•Antigen presentation defects may render MSI tumors resistant to checkpoint blockade
Proteogenomic analyses of prospectively collected endometrial carcinomas provide insights into the role of underlying molecular pathways and the immune landscape that drive disease.
Abstract
At the core of immunotherapy is the T cell recognition of tumor antigens. Thus, comprehensive characterization of tumor antigens is essential for the design of effective and safe cancer ...immunotherapy strategies. Mass spectrometry (MS)-based immunopeptidomics allows high-throughput, direct identification of major histocompatibility complex (MHC)-bound peptides in vivo. Here, we collected 42 published human immunopeptidomic datasets, which include 327 cancer samples covering nine cancer types and 216 non-cancerous samples. A systematic, quality-controlled analysis of all 51.6 million MS/MS spectra using an open search algorithm identified 364,283 peptides, including 11,647 modified peptides associated with 80 types of modifications. Unmodified peptides showed high levels of predicted binding affinities by NetMHCpan; however, the predicted binding affinities for the modified peptides were much lower, suggesting a deficiency of existing computational tools in making predictions for modified peptides. Analysis of the 416 phosphorylated and 1,239 acetylated HLA class I peptides revealed distinct sequence motifs, and the pattern for the phosphopeptides was consistent with previous reports. Further interrogation of all identified peptides revealed evidence for tumor specific-presentation of hundreds of known and novel cancer-testis antigens as well as tumor associated antigens. We also found non-tumor-specific presentation of 44 previously annotated cancer-testis antigens. Applying NeoQuery, a newly developed computational pipeline, to our dataset identified immunopeptidomic evidence for more than 1,000 somatic mutation-derived neoantigens, and a subset of them were further validated through a traditional MS/MS peptide identification pipeline. We make all these data together with annotated MS/MS spectra supporting each individual antigen identification in a publicly accessible, easily browsable web portal named cancer antigen atlas (caAtlas, http://www.zhang-lab.org/caatlas/). caAtlas provides a fundamental resource for the selection and prioritization of MHC-bound peptides for immunogenicity testing and cancer immunotherapy development.
Citation Format: Xinpei Yi, Yuxing Liao, Bo Wen, Kai Li, Yongchao Dou, Sara R. Savage, Bing Zhang. caAtlas: An immunopeptidome atlas of human cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1895.
To improve the understanding of chemo-refractory high-grade serous ovarian cancers (HGSOCs), we characterized the proteogenomic landscape of 242 (refractory and sensitive) HGSOCs, representing one ...discovery and two validation cohorts across two biospecimen types (formalin-fixed paraffin-embedded and frozen). We identified a 64-protein signature that predicts with high specificity a subset of HGSOCs refractory to initial platinum-based therapy and is validated in two independent patient cohorts. We detected significant association between lack of Ch17 loss of heterozygosity (LOH) and chemo-refractoriness. Based on pathway protein expression, we identified 5 clusters of HGSOC, which validated across two independent patient cohorts and patient-derived xenograft (PDX) models. These clusters may represent different mechanisms of refractoriness and implicate putative therapeutic vulnerabilities.
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•A comprehensive proteogenomic analysis of 242 HGSOC tumors was performed•A lack of Chr17-LOH was observed to be associated with refractoriness•A 64-protein signature predicts refractoriness in multiple tumor cohorts•Pathway-based clustering reveals 5 subtypes validated in independent cohorts
Patients with high-grade serous ovarian cancers (HGSOCs) have a poor outcome, with the standard of care not having changed over the decades. A detailed characterization of the proteogenomic landscape of HGSOCs across multiple cohorts and validation studies identifies a distinct signature that predicts with high specificity a subset of patients with chemotherapy-refractory cancers and implicates potential therapeutic vulnerabilities.
TNFalpha has been identified as playing an important role in pathologic complications associated with diabetic retinopathy and retinal inflammation, such as retinal leukostasis. However, the ...transcriptional effects of TNFalpha on retinal microvascular endothelial cells and the different signaling pathways involved are not yet fully understood. In the present study, RNA-seq was used to profile the transcriptome of human retinal microvascular endothelial cells (HRMEC) treated for 4 hours with TNFalpha in the presence or absence of the NFAT-specific inhibitor INCA-6, in order to gain insight into the specific effects of TNFalpha on RMEC and identify any involvement of NFAT signaling. Differential expression analysis revealed that TNFalpha treatment significantly upregulated the expression of 579 genes when compared to vehicle-treated controls, and subsequent pathway analysis revealed a TNFalpha-induced enrichment of transcripts associated with cytokine-cytokine receptor interactions, cell adhesion molecules, and leukocyte transendothelial migration. Differential expression analysis comparing TNFalpha-treated cells to those co-treated with INCA-6 revealed 10 genes whose expression was significantly reduced by the NFAT inhibitor, including those encoding the proteins VCAM1 and CX3CL1 and cytokines CXCL10 and CXCL11. This study identifies the transcriptional effects of TNFalpha on HRMEC, highlighting its involvement in multiple pathways that contribute to retinal leukostasis, and identifying a previously unknown role for NFAT-signaling downstream of TNFalpha.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Pancreatic cancer is one of the deadliest cancers and the five-year survival rate is less than 10%. Pancreatic ductal adenocarcinoma (PDAC) represents more than 90% of all pancreatic ...malignancies, and is responsible for the majority of pancreatic cancer-related deaths. Towards understanding the underlying molecular alterations that drive PDAC oncogenesis and identify therapeutic targets for personalized treatments, we comprehensively characterized 140 pancreatic cancers and 67 normal adjacent tissues. To ensure robust, downstream analyses, tumor neoplastic cellularity was assessed via multiple, orthogonal strategies using molecular features, and verified via pathological estimation of tumor cellularity based on histological review to select tumors with sufficient tumor cellularity. We also included the analysis of 9 normal pancreatic ductal tissues. Proteomic, phosphoproteomic, and glycoproteomic analyses were used to characterize proteins and their modifications. In addition, whole genome sequencing, whole exome sequencing, methylation, RNA-seq, and miRNA-seq were performed on the same tissues to facilitate an integrated proteogenomic analysis and determine the impact of genomic alterations on protein expression, signaling pathways, and post-translational modifications. These characterizations revealed functional impacts of genomic and epigenomic alterations on proteins and protein modifications, delineated PDAC cell microenvironment compositions and the immune signatures for immunotherapy, also uncovered putative kinase inhibitors that could be tested for therapy. This integrated proteogenomic characterization of PDAC will serve as a valuable resource for the community, paving the way for early detection and identification of novel therapeutic targets.
Citation Format: Liwei Cao, Chen Huang, Daniel Cui Zhou, Yingwei Hu, Mamie Lih, Sara R. Savage, Karsten Krug, David J. Clark, Michael Schnaubelt, Lijun Chen, Felipe da Veiga Leprevost, Rodrigo Vargas Eguez, Alexey I. Nesvizhskii, D.R. Mani, Gilbert S. Omenn, Emily S. Boja, Mehdi Mesri, Ana I. Robles, Henry Rodriguez, Oliver F. Bathe, Daniel W. Chan, Ralph H. Hruban, Li Ding, Bing Zhang, Hui Zhang, Clinical Proteomic Tumor Analysis Consortium. Proteogenomic characterizations of pancreatic ductal adenocarcinoma abstract. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr IA-003.
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