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Proteogenomic data and resources for pan-cancer analysis
Li, Yize; Dou, Yongchao; Da Veiga Leprevost, Felipe; Geffen, Yifat; Calinawan, Anna P; Aguet, François; Akiyama, Yo; Anand, Shankara; Birger, Chet; Cao, Song; Chaudhary, Rekha; Chilappagari, Padmini; Cieslik, Marcin; Colaprico, Antonio; Zhou, Daniel Cui; Day, Corbin; Domagalski, Marcin J; Esai Selvan, Myvizhi; Fenyö, David; Foltz, Steven M; Francis, Alicia; Gonzalez-Robles, Tania; Gümüş, Zeynep H; Heiman, David; Holck, Michael; Hong, Runyu; Hu, Yingwei; Jaehnig, Eric J; Ji, Jiayi; Jiang, Wen; Katsnelson, Lizabeth; Ketchum, Karen A; Klein, Robert J; Lei, Jonathan T; Liang, Wen-Wei; Liao, Yuxing; Lindgren, Caleb M; Ma, Weiping; Ma, Lei; MacCoss, Michael J; Martins Rodrigues, Fernanda; McKerrow, Wilson; Nguyen, Ngoc; Oldroyd, Robert; Pilozzi, Alexander; Pugliese, Pietro; Reva, Boris; Rudnick, Paul; Ruggles, Kelly V; Rykunov, Dmitry; Savage, Sara R; Schnaubelt, Michael; Schraink, Tobias; Shi, Zhiao; Singhal, Deepak; Song, Xiaoyu; Storrs, Erik; Terekhanova, Nadezhda V; Thangudu, Ratna R; Thiagarajan, Mathangi; Wang, Liang-Bo; Wang, Joshua M; Wang, Ying; Wen, Bo; Wu, Yige; Wyczalkowski, Matthew A; Xin, Yi; Yao, Lijun; Yi, Xinpei; Zhang, Hui; Zhang, Qing; Zuhl, Maya; Getz, Gad; Ding, Li; Nesvizhskii, Alexey I; Wang, Pei; Robles, Ana I; Zhang, Bing; Payne, Samuel H; ,
The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) investigates tumors from a proteogenomic perspective, creating rich multi-omics datasets connecting genomic aberrations to cancer phenotypes. To facilitate pan-cancer investigations, we have generated harmonized genomic, transcriptomic, proteomic, and clinical data for >1000 tumors in 10 cohorts to create a cohesive and powerful dataset for scientific discovery. We outline efforts by the CPTAC pan-cancer working group in data harmonization, data dissemination, and computational resources for aiding biological discoveries. We also discuss challenges for multi-omics data integration and analysis, specifically the unique challenges of working with both nucleotide sequencing and mass spectrometry proteomics data.
PMCID:10506762
PMID: 37582339
ISSN: 1878-3686
CID: 5595612
An inflammatory transcriptomic signature in psoriasis associates with future cardiovascular events
Garshick, Michael S; Barrett, Tessa J; Cornwell, MacIntosh G; Drenkova, Kamelia; Garelik, Jessica; Weber, Brittany N; Schlamp, Florencia; Rockman, Caron; Ruggles, Kelly V; Reynolds, Harmony R; Berger, Jeffrey S
BACKGROUND:Psoriasis is an inflammatory skin disease associated with increased cardiovascular (CV) risk, whose pathogenesis is not fully known. OBJECTIVE:We identified a transcriptomic signature in psoriasis and investigated its association with prevalent and future risk of a CV event to understand the connection between psoriasis and CV disease (CVD). METHODS:Psoriasis patients (n = 37) with a history of moderate-severe skin disease without CVD and 11 matched controls underwent whole blood RNA sequencing. This transcriptomic signature in psoriasis versus controls was evaluated in two CVD cohorts: Women referred for cardiac catheterization with (n = 76) versus without (n = 97) myocardial infarction (MI), and patients with peripheral artery disease (n = 106) followed over 2.5 years for major adverse CV or limb events (MACLE). The association between genes differentially expressed in psoriasis and prevalent and incident CV events was assed. RESULTS:In psoriasis, median age was 44 (IQR; 34-51) years, 49% male and ACC/AHA ASCVD Risk Score of 1.0% (0.6-3.4) with no significant difference versus controls. The median psoriasis area and severity index score (PASI) was 4.0 (IQR 2.9-8.2) with 36% on biologic therapy. Overall, 247 whole blood genes were upregulated and 228 downregulated in psoriasis versus controls (p < 0.05), and 1302 genes positively and 1244 genes negatively correlated with PASI (p < 0.05). Seventy-three genes overlapped between psoriasis prevalence and PASI with key regulators identified as IL-6, IL-1β and interferon gamma. In the CVD cohorts, 50 of 73 genes (68%) identified in psoriasis associated with prevalent MI, and 29 (40%) with incident MACLE. Key regulator transcripts identified in psoriasis and CVD cohorts included SOCS3, BCL3, OSM, PIM2, PIM3 and STAT5A. CONCLUSIONS:A whole blood transcriptomic signature of psoriasis diagnosis and severity associated with prevalent MI and incident MACLE. These data have implications for better understanding the link between psoriasis, systemic inflammation and CVD.
PMID: 36924033
ISSN: 1468-3083
CID: 5462522
PhosphoDisco: a toolkit for co-regulated phosphorylation module discovery in phosphoproteomic data
Schraink, Tobias; Blumenberg, Lili; Hussey, Grant; George, Sabrina; Miller, Brecca; Mathew, Nithu; González-Robles, Tania J; Sviderskiy, Vladislav; Papagiannakopoulos, Thales; Possemato, Richard; Fenyö, David; Ruggles, Kelly V
Kinases are key players in cancer-relevant pathways and are the targets of many successful precision cancer therapies (1, 2). Phosphoproteomics is a powerful approach to study kinase activity and has been used increasingly for the characterization of tumor samples leading to the identification of novel chemotherapeutic targets and biomarkers (3-10). Finding co-regulated phosphorylation sites which represent potential kinase-substrate sets or members of the same signaling pathway allows us to harness this data to identify clinically relevant and targetable alterations in signaling cascades. Unfortunately, studies have found that databases of co-regulated phosphorylation sites (11, 12) are only experimentally supported in a small number of substrate sets (13, 14). To address the inherent challenge of defining co-regulated phosphorylation modules relevant to a given dataset, we developed PhosphoDisco, a toolkit for determining co-regulated phosphorylation modules. We applied this approach to tandem mass spectrometry based phosphoproteomic data for breast and non-small cell lung cancer and identified canonical as well as putative new phosphorylation site modules. Our analysis identified several interesting modules in each cohort. Among these was a new cell cycle checkpoint module enriched in basal breast cancer samples and a module of PRKC isozymes putatively co-regulated by CDK12 in lung cancer. We demonstrate that modules defined by PhosphoDisco can be used to further personalized cancer treatment strategies by establishing active signaling pathways in a given patient tumor or set of tumors, and in providing new ways to classify tumors based on signaling activity.
PMID: 37394063
ISSN: 1535-9484
CID: 5538912
Platelet LGALS3BP Induces Myeloid Inflammation In Systemic Lupus Erythematosus
El Bannoudi, Hanane; Cornwell, MacIntosh; Luttrell-Williams, Elliot; Engel, Alexis; Rolling, Christina; Barrett, Tessa J; Izmirly, Peter; Belmont, H Michael; Ruggles, Kelly; Clancy, Robert; Buyon, Jill; Berger, Jeffrey S
OBJECTIVE:Platelets are mediators of inflammation with immune effector cell properties, and have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). This study investigated the role of platelet associated lectin galactoside-binding soluble 3 binding protein (LGALS3BP) as a mediator of inflammation in SLE, and a potential biomarker associated with clinical phenotypes. METHODS:We performed RNA sequencing on platelets of patients with SLE (n=54) and age, sex, and race-matched controls (n=18) and measured LGALS3BP in platelet releasate and in circulating serum. We investigated the association between levels of LGALS3BP with the prevalence, disease severity, and clinical phenotpyes of SLE, and studied platelet-mediated effects on myeloid inflammation. RESULTS:). Platelet-released LGALS3BP was highly correlated with circulating LGALS3BP (R = 0.69, p < 0.0001). Circulating LGALS3BP correlated with the SLE disease activity index (R = 0.32, p = 0.0006). Specifically, circulating LGALS3BP was higher in SLE patients with lupus nephritis than those with inactive disease (4.0 μg/mL vs 2.3 μg/mL, P < 0.001). IFN-α induced LGALS3BP transcription and translation in a megakaryoblastic cell line (MEG-01) cells in a dose-dependent manner. Recombinant LGALS3BP and platelet releasates from SLE patients enhanced pro-inflammatory cytokine production by macrophages. CONCLUSIONS:These data support that platelets act as potent effector cells contributing to the pathogenesis of SLE by secreting proinflammatory LGALS3BP, which also represents a novel biomarker of SLE clinical activity.
PMID: 36245285
ISSN: 2326-5205
CID: 5360062
Modeling of clinical phenotypes in systemic lupus erythematosus based on the platelet transcriptome and FCGR2a genotype
Cornwell, MacIntosh G; Bannoudi, Hanane El; Luttrell-Williams, Elliot; Engel, Alexis; Barrett, Tessa J; Myndzar, Khrystyna; Izmirly, Peter; Belmont, H Michael; Clancy, Robert; Ruggles, Kelly V; Buyon, Jill P; Berger, Jeffrey S
BACKGROUND:The clinical heterogeneity of SLE with its complex pathogenesis remains challenging as we strive to provide optimal management. The contribution of platelets to endovascular homeostasis, inflammation and immune regulation highlights their potential importance in SLE. Prior work from our group showed that the Fcγ receptor type IIa (FcγRIIa)-R/H131 biallelic polymorphism is associated with increased platelet activity and cardiovascular risk in SLE. The study was initiated to investigate the platelet transcriptome in patients with SLE and evaluate its association across FcγRIIa genotypes and distinct clinical features. METHODS:Fifty-one patients fulfilling established criteria for SLE (mean age = 41.1 ± 12.3, 100% female, 45% Hispanic, 24% black, 22% Asian, 51% white, mean SLEDAI = 4.4 ± 4.2 at baseline) were enrolled and compared with 18 demographically matched control samples. The FCGR2a receptor was genotyped for each sample, and RNA-seq was performed on isolated, leukocyte-depleted platelets. Transcriptomic data were used to create a modular landscape to explore the differences between SLE patients and controls and various clinical parameters in the context of FCGR2a genotypes. RESULTS:There were 2290 differentially expressed genes enriched for pathways involved in interferon signaling, immune activation, and coagulation when comparing SLE samples vs controls. When analyzing patients with proteinuria, modules associated with oxidative phosphorylation and platelet activity were unexpectedly decreased. Furthermore, genes that were increased in SLE and in patients with proteinuria were enriched for immune effector processes, while genes increased in SLE but decreased in proteinuria were enriched for coagulation and cell adhesion. A low-binding FCG2Ra allele (R131) was associated with decreases in FCR activation, which further correlated with increases in platelet and immune activation pathways. Finally, we were able to create a transcriptomic signature of clinically active disease that performed significantly well in discerning SLE patients with active clinical disease form those with inactive clinical disease. CONCLUSIONS:In aggregate, these data demonstrate the platelet transcriptome provides insight into lupus pathogenesis and disease activity, and shows potential use as means of assessing this complex disease using a liquid biopsy.
PMCID:10082503
PMID: 37029410
ISSN: 1479-5876
CID: 5459472
The Sin3B chromatin modifier restricts cell cycle progression to dictate hematopoietic stem cell differentiation
Calderon, Alexander; Mestvirishvili, Tamara; Boccalatte, Francesco; Ruggles, Kelly; David, Gregory
To maintain blood homeostasis, millions of terminally differentiated effector cells are produced every day. At the apex of this massive and constant blood production lie hematopoietic stem cells (HSCs), a rare cell type harboring unique self-renewal and multipotent properties. A key feature of HSCs is their ability to temporarily exit the cell cycle in a state termed quiescence. Defective control of cell cycle progression can eventually lead to bone marrow failure or malignant transformation. Recent work in embryonic stem cells has suggested that cells can more robustly respond to differentiation cues in the early phases of the cell cycle, owing to a discrete chromatin state permissive to cell fate commitment. However, the molecular mechanisms tying cell cycle re-entry to cell fate commitment in adult stem cells such as HSCs remain elusive. Here, we report that the chromatin-associated Sin3B protein is necessary for HSCs' commitment to differentiation, but dispensable for their self-renewal or survival. Transcriptional profiling of hematopoietic stem and progenitor cells (HSPCs) genetically inactivated for Sin3B at the single cell level reveals aberrant cell cycle gene expression, correlating with the defective engagement of discrete signaling programs. In particular, the loss of Sin3B in the hematopoietic compartment results in aberrant expression of cell adhesion molecules and essential components of the interferon signaling cascade in LT-HSCs. Finally, chromatin accessibility profiling in LT-HSCs suggests a link between Sin3B-dependent cell cycle progression and priming of hematopoietic stem cells for differentiation. Together, these results point to controlled progression through the G1 phase of the cell cycle as a likely regulator of HSC lineage commitment through the modulation of chromatin features.
PMCID:9900761
PMID: 36747851
CID: 5602942
Pathogen-Specific Alterations in the Gut Microbiota Predict Outcomes in Flare of Inflammatory Bowel Disease Complicated by Gastrointestinal Infection
Axelrad, Jordan E; Chen, Ze; Devlin, Joseph; Ruggles, Kelly V; Cadwell, Ken
INTRODUCTION/BACKGROUND:Enteric infection with Clostridioides difficile , Escherichia coli subtypes, and norovirus is commonly detected in flares of inflammatory bowel disease (IBD). We associated the gut microbiome during flare complicated by a gastrointestinal pathogen with outcomes of IBD. METHODS:We performed a cross-sectional study of 260 patients (92 IBD and 168 non-IBD) with a gastrointestinal polymerase chain reaction panel positive for C. difficile, E. coli , or norovirus, or negative during an episode of diarrhea from 2018 to 2020, and 25 healthy controls. Clinical variables, IBD status, and 2-year outcomes were collected. Using 16S rRNA sequencing, we measured the effect size of the gut microbiome on IBD characteristics and outcomes. RESULTS:There were major differences in the gut microbiome between patients with and without a pathogen and IBD. In IBD, a higher proportion of patients without a pathogen required hospitalization and IBD therapies at flare and within the 2 years after flare, driven by a milder disease course in flares complicated by an E. coli subtype or norovirus. Examining the contribution of clinical covariates, the presence of IBD, and C-reactive protein, C. difficile had a greater relative influence on the gut microbiome compared with the presence of an E. coli subtype or norovirus. In patients with C. difficile or no pathogen, lower microbiome diversity at flare was associated with adverse IBD outcomes over 2 years. DISCUSSION/CONCLUSIONS:Distinctive pathogen-specific gut microbiomes were associated with subsequent IBD outcomes. These findings may have direct implications for the management of IBD flares complicated by enteric pathogens.
PMCID:9945377
PMID: 36729813
ISSN: 2155-384x
CID: 5426732
Syndemic factors associated with non-fatal overdose among young opioid users in New York City
Guarino, Honoria; Frank, David; Quinn, Kelly; Kim, Dongah; Gile, Krista; Ruggles, Kelly; Friedman, Samuel R; Mateu-Gelabert, Pedro
INTRODUCTION:Rates of illicit opioid use are particularly high among young adults, yet research on overdose experience and factors associated with overdose in this population remains limited. This study examines the experiences and correlates of non-fatal overdose among young adults using illicit opioids in New York City (NYC). METHODS:539 participants were recruited via Respondent-Driven Sampling in 2014-2016. Eligibility criteria included: aged 18-29 years old; current residence in NYC; and nonmedical prescription opioid (PO) use and/or heroin use in the past 30 days. Participants completed structured interviews to assess their socio-demographics, drug use trajectories, current substance use and lifetime and most recent overdose experiences, and were tested on-site for hepatitis C virus (HCV) antibodies. RESULTS:43.9% of participants reported lifetime overdose experience; of these, 58.8% had experienced two or more overdose events. The majority of participants' most recent overdoses (63.5%) were due to polysubstance use. In bivariable analyses, after RDS adjustment, having ever overdosed was correlated with: household income of >$100,00 growing up (vs. $51,000-100,000); lifetime homelessness; HCV antibody-positive status; lifetime engagement in regular nonmedical benzodiazepine use, regular heroin injection and regular PO injection; and using a non-sterile syringe in the past 12 months. Multivariable logistic regression identified childhood household income >$100,00 (AOR=1.88), HCV-positive status (AOR=2.64), benzodiazepine use (AOR=2.15), PO injection (AOR=1.96) and non-sterile syringe use (AOR=1.70) as significant independent correlates of lifetime overdose. A multivariable model with multiple overdoses (vs. one) found only lifetime regular heroin use and PO injection to be strong correlates. DISCUSSION:Results indicate a high prevalence of lifetime and repeated overdose among opioid-using young adults in NYC, highlighting a need for intensified overdose prevention efforts for this population. The strong associations of HCV and indices of polydrug use with overdose suggest that prevention efforts should address the complex risk environment in which overdose occurs, attending to the overlapping nature of disease-related risk behavior and overdose risk behavior among young people who inject opioids. Overdose prevention efforts tailored for this group may find it useful to adopt a syndemic conception of overdose that understands such events as resulting from multiple, and often interrelated, risk factors.
PMCID:10332320
PMID: 37435512
ISSN: 2296-2565
CID: 5537062
Clostridia isolated from helminth-colonized humans promote the life cycle of Trichuris species
Sargsian, Shushan; Chen, Ze; Lee, Soo Ching; Robertson, Amicha; Thur, Rafaela Saes; Sproch, Julia; Devlin, Joseph C; Tee, Mian Zi; Er, Yi Xian; Copin, Richard; Heguy, Adriana; Pironti, Alejandro; Torres, Victor J; Ruggles, Kelly V; Lim, Yvonne A L; Bethony, Jeffrey; Loke, P'ng; Cadwell, Ken
Soil-transmitted intestinal worms known as helminths colonize over 1.5 billion people worldwide. Although helminth colonization has been associated with altered composition of the gut microbiota, such as increases in Clostridia, individual species have not been isolated and characterized. Here, we isolate and sequence the genome of 13 Clostridia from the Orang Asli, an indigenous population in Malaysia with a high prevalence of helminth infections. Metagenomic analysis of 650 fecal samples from urban and rural Malaysians confirm the prevalence of species corresponding to these isolates and reveal a specific association between Peptostreptococcaceae family members and helminth colonization. Remarkably, Peptostreptococcaceae isolated from the Orang Asli display superior capacity to promote the life cycle of whipworm species, including hatching of eggs from Trichuris muris and Trichuris trichiura. These findings support a model in which helminths select for gut colonization of microbes that support their life cycle.
PMID: 36450245
ISSN: 2211-1247
CID: 5374022
The γδ IEL effector API5 masks genetic susceptibility to Paneth cell death
Matsuzawa-Ishimoto, Yu; Yao, Xiaomin; Koide, Akiko; Ueberheide, Beatrix M; Axelrad, Jordan E; Reis, Bernardo S; Parsa, Roham; Neil, Jessica A; Devlin, Joseph C; Rudensky, Eugene; Dewan, M Zahidunnabi; Cammer, Michael; Blumberg, Richard S; Ding, Yi; Ruggles, Kelly V; Mucida, Daniel; Koide, Shohei; Cadwell, Ken
Loss of Paneth cells and their antimicrobial granules compromises the intestinal epithelial barrier and is associated with Crohn's disease, a major type of inflammatory bowel disease1-7. Non-classical lymphoid cells, broadly referred to as intraepithelial lymphocytes (IELs), intercalate the intestinal epithelium8,9. This anatomical position has implicated them as first-line defenders in resistance to infections, but their role in inflammatory disease pathogenesis requires clarification. The identification of mediators that coordinate crosstalk between specific IEL and epithelial subsets could provide insight into intestinal barrier mechanisms in health and disease. Here we show that the subset of IELs that express γ and δ T cell receptor subunits (γδ IELs) promotes the viability of Paneth cells deficient in the Crohn's disease susceptibility gene ATG16L1. Using an ex vivo lymphocyte-epithelium co-culture system, we identified apoptosis inhibitor 5 (API5) as a Paneth cell-protective factor secreted by γδ IELs. In the Atg16l1-mutant mouse model, viral infection induced a loss of Paneth cells and enhanced susceptibility to intestinal injury by inhibiting the secretion of API5 from γδ IELs. Therapeutic administration of recombinant API5 protected Paneth cells in vivo in mice and ex vivo in human organoids with the ATG16L1 risk allele. Thus, we identify API5 as a protective γδ IEL effector that masks genetic susceptibility to Paneth cell death.
PMID: 36198790
ISSN: 1476-4687
CID: 5351622