ORCID Profile
0000-0002-8876-128X
Current Organisation
Peking University Cancer Hospital & Institute
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Publisher: American Association for the Advancement of Science (AAAS)
Date: 28-02-2020
Abstract: We performed the multi-omic characterization of gastric cancer to detect key molecular features for neoadjuvant chemotherapy.
Publisher: Oxford University Press (OUP)
Date: 24-11-2020
DOI: 10.1093/NAR/GKAA1075
Abstract: Protein–protein interactions (PPIs) are crucial to mediate biological functions, and understanding PPIs in cancer type-specific context could help decipher the underlying molecular mechanisms of tumorigenesis and identify potential therapeutic options. Therefore, we update the Protein Interaction Network Analysis (PINA) platform to version 3.0, to integrate the unified human interactome with RNA-seq transcriptomes and mass spectrometry-based proteomes across tens of cancer types. A number of new analytical utilities were developed to help characterize the cancer context for a PPI network, which includes inferring proteins with expression specificity and identifying candidate prognosis biomarkers, putative cancer drivers, and therapeutic targets for a specific cancer type as well as identifying pairs of co-expressing interacting proteins across cancer types. Furthermore, a brand-new web interface has been designed to integrate these new utilities within an interactive network visualization environment, which allows users to quickly and comprehensively investigate the roles of human interacting proteins in a cancer type-specific context. PINA is freely available at ina/.
Publisher: Springer Science and Business Media LLC
Date: 15-02-2017
DOI: 10.1038/NATURE21063
Abstract: The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
Publisher: Springer Science and Business Media LLC
Date: 24-02-2016
DOI: 10.1038/NATURE16965
Abstract: Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous (2) pancreatic progenitor (3) immunogenic and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2013
DOI: 10.1158/0008-5472.CAN-12-3359
Abstract: The exocrine pancreas can undergo acinar-to-ductal metaplasia (ADM), as in the case of pancreatitis where precursor lesions of pancreatic ductal adenocarcinoma (PDAC) can arise. The NAD+-dependent protein deacetylase Sirtuin-1 (Sirt1) has been implicated in carcinogenesis with dual roles depending on its subcellular localization. In this study, we examined the expression and the role of Sirt1 in different stages of pancreatic carcinogenesis, i.e. ADM models and established PDAC. In addition, we analyzed the expression of KIAA1967, a key mediator of Sirt1 function, along with potential Sirt1 downstream targets. Sirt1 was co-expressed with KIAA1967 in the nuclei of normal pancreatic acinar cells. In ADM, Sirt1 underwent a transient nuclear-to-cytoplasmic shuttling. Experiments where during ADM, we enforced repression of Sirt1 shuttling, inhibition of Sirt1 activity or modulation of its expression, all underscore that the temporary decrease of nuclear and increase of cytoplasmic Sirt1 stimulate ADM. Our results further underscore that important transcriptional regulators of acinar differentiation, that is, Pancreatic transcription factor-1a and β-catenin can be deacetylated by Sirt1. Inhibition of Sirt1 is effective in suppression of ADM and in reducing cell viability in established PDAC tumors. KIAA1967 expression is differentially downregulated in PDAC and impacts on the sensitivity of PDAC cells to the Sirt1/2 inhibitor Tenovin-6. In PDAC, acetylation of β-catenin is not affected, unlike p53, a well-characterized Sirt1-regulated protein in tumor cells. Our results reveal that Sirt1 is an important regulator and potential therapeutic target in pancreatic carcinogenesis. Cancer Res 73(7) 2357–67. ©2012 AACR.
Publisher: Springer Science and Business Media LLC
Date: 13-07-2021
DOI: 10.1038/S41467-021-24585-9
Abstract: Despite long being considered as “junk”, transposable elements (TEs) are now accepted as catalysts of evolution. One ex le is Mutator -like elements (MULEs, one type of terminal inverted repeat DNA TEs, or TIR TEs) capturing sequences as Pack-MULEs in plants. However, their origination mechanism remains perplexing, and whether TIR TEs mediate duplication in animals is almost unexplored. Here we identify 370 Pack-TIRs in 100 animal reference genomes and one Pack-TIR ( Ssk-FB4 ) family in fly populations. We find that single-copy Pack-TIRs are mostly generated via transposition-independent gap filling, and multicopy Pack-TIRs are likely generated by transposition after replication fork switching. We show that a proportion of Pack-TIRs are transcribed and often form chimeras with hosts. We also find that Ssk-FB4s represent a young protein family, as supported by proteomics and signatures of positive selection. Thus, TIR TEs catalyze new gene structures and new genes in animals via both transposition-independent and -dependent mechanisms.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 25-07-2018
DOI: 10.1126/SCITRANSLMED.AAT3504
Abstract: Inhibition of activin signaling enhances the efficacy and safety of platinum chemotherapy in lung adenocarcinoma models.
Publisher: Oxford University Press (OUP)
Date: 08-11-2011
DOI: 10.1093/NAR/GKR967
Publisher: Oxford University Press (OUP)
Date: 07-2006
DOI: 10.1093/NAR/GKL167
Publisher: Wiley
Date: 19-09-2017
DOI: 10.1002/PATH.4932
Abstract: Gastro-oesophageal junction (GEJ) carcinoma and distal gastric cancer (GC) have distinct epidemiology and clinical features and their relationship is uncertain. Synchronous multiple gastric cancers located mostly at proximal and distal sites provide rare specimens for investigating the comprehensive genomic relationships among these cancers in the context of identical genetic circumstances. Formalin-fixed, paraffin-embedded (FFPE) s les from 12 patients with synchronous GEJ carcinoma and distal GC were collected in this study. Whole-exome sequencing (WES) was performed using normal tissues as a control. Mutational profiling, clonality analysis, a detailed clinico-pathological review, determination of MSI status, EBER in situ hybridization (ISH), and programmed cell death 1 (PD-1) rogrammed death-ligand 1 (PD-L1) immunohistochemical staining were performed. Twenty-three of the 24 s les were microsatellite-stable (MSS). Subclonal analysis revealed that nine pairs of GEJ and distal GC tumours in neoadjuvant chemotherapy naïve patients developed independently from different origins. Two patients who received neoadjuvant chemotherapy shared clonal origins with highly similar somatic alterations. The remaining one patient who shared a rare mutation died within 6.2 months at the N3 stage. However, the enriched pathway identified from the overall mutation spectra in distal GC and GEJ carcinoma showed the close relationship of these cancers. Thus, although these cancers may have similar characteristics, histopathological and genetic profiling from single tumour specimens may still underestimate the mutational burden and somatic heterogeneity of multiple GCs. In addition, this series of cases also showed a PD-L1 expression rate of 58.3% and 66.7% in distal GC and GEJ carcinoma, respectively, with all the cases expressing PD-1. This result suggests the potential benefit of immunotherapeutic treatments. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Publisher: Springer Science and Business Media LLC
Date: 08-05-2017
DOI: 10.1038/NCOMMS15158
Abstract: Host cell signalling during infection with intracellular pathogens remains poorly understood. Here we report on the use of antibody microarray technology to detect variations in the expression levels and phosphorylation status of host cell signalling proteins during hepatitis C virus (HCV) replication. Following transfection with HCV RNA, the JNK and NF-κB pathways are suppressed, while the JAK/STAT5 pathway is activated furthermore, components of the apoptosis and cell cycle control machineries are affected in the expression and/or phosphorylation status. RNAi-based hit validation identifies components of the JAK/STAT, NF-κB, MAPK and calcium-induced pathways as modulators of HCV replication. Selective chemical inhibition of one of the identified targets, the JNK activator kinase MAP4K2, does impair HCV replication. Thus this study provides a comprehensive picture of host cell pathway mobilization by HCV and uncovers potential therapeutic targets. The strategy of identifying targets for anti-infective intervention within the host cell signalome can be applied to any intracellular pathogen.
Publisher: BMJ
Date: 21-10-2014
DOI: 10.1136/GUTJNL-2014-307075
Abstract: The transcription factor SOX9 was recently shown to stimulate ductal gene expression in pancreatic acinar-to-ductal metaplasia and to accelerate development of premalignant lesions preceding pancreatic ductal adenocarcinoma (PDAC). Here, we investigate how SOX9 operates in pancreatic tumourigenesis. We analysed genomic and transcriptomic data from surgically resected PDAC and extended the expression analysis to xenografts from PDAC s les and to PDAC cell lines. SOX9 expression was manipulated in human cell lines and mouse models developing PDAC. We found genetic aberrations in the SOX9 gene in about 15% of patient tumours. Most PDAC s les strongly express SOX9 protein, and SOX9 levels are higher in classical PDAC. This tumour subtype is associated with better patient outcome, and cell lines of this subtype respond to therapy targeting epidermal growth factor receptor (EGFR/ERBB1) signalling, a pathway essential for pancreatic tumourigenesis. In human PDAC, high expression of SOX9 correlates with expression of genes belonging to the ERBB pathway. In particular, ERBB2 expression in PDAC cell lines is stimulated by SOX9. Inactivating Sox9 expression in mice confirmed its role in PDAC initiation it demonstrated that Sox9 stimulates expression of several members of the ERBB pathway and is required for ERBB signalling activity. By integrating data from patient s les and mouse models, we found that SOX9 regulates the ERBB pathway throughout pancreatic tumourigenesis. Our work opens perspectives for therapy targeting tumourigenic mechanisms.
Publisher: Oxford University Press (OUP)
Date: 22-05-2009
DOI: 10.1093/NAR/GKP428
Publisher: Elsevier BV
Date: 04-2014
Publisher: Springer Science and Business Media LLC
Date: 25-02-2015
DOI: 10.1038/NATURE14169
Publisher: BMJ
Date: 09-04-2014
Publisher: Elsevier BV
Date: 2022
Publisher: Springer Science and Business Media LLC
Date: 30-11-2018
DOI: 10.1038/S41467-018-07497-Z
Abstract: Whereas genomic aberrations in the SLIT-ROBO pathway are frequent in pancreatic ductal adenocarcinoma (PDAC), their function in the pancreas is unclear. Here we report that in pancreatitis and PDAC mouse models, epithelial Robo2 expression is lost while Robo1 expression becomes most prominent in the stroma. Cell cultures of mice with loss of epithelial Robo2 (Pdx1 Cre Robo2 F/F ) show increased activation of Robo1 + myofibroblasts and induction of TGF-β and Wnt pathways. During pancreatitis, Pdx1 Cre Robo2 F/F mice present enhanced myofibroblast activation, collagen crosslinking, T-cell infiltration and tumorigenic immune markers. The TGF-β inhibitor galunisertib suppresses these effects. In PDAC patients, ROBO2 expression is overall low while ROBO1 is variably expressed in epithelium and high in stroma. ROBO2 low ROBO1 high patients present the poorest survival. In conclusion, Robo2 acts non-autonomously as a stroma suppressor gene by restraining myofibroblast activation and T-cell infiltration. ROBO1/2 expression in PDAC patients may guide therapy with TGF-β inhibitors or other stroma /immune modulating agents.
Publisher: Springer Science and Business Media LLC
Date: 24-10-2012
DOI: 10.1038/NATURE11547
Publisher: Oxford University Press (OUP)
Date: 08-2023
DOI: 10.1093/BIB/BBAD267
Abstract: Adequate reporting is essential for evaluating the performance and clinical utility of a prognostic prediction model. Previous studies indicated a prevalence of incomplete or suboptimal reporting in translational and clinical studies involving development of multivariable prediction models for prognosis, which limited the potential applications of these models. While reporting templates introduced by the established guidelines provide an invaluable framework for reporting prognostic studies uniformly, there is a widespread lack of qualified adherence, which may be due to miscellaneous challenges in manual reporting of extensive model details, especially in the era of precision medicine. Here, we present ReProMSig (Reproducible Prognosis Molecular Signature), a web-based integrative platform providing the analysis framework for development, validation and application of a multivariable prediction model for cancer prognosis, using clinicopathological features and/or molecular profiles. ReProMSig platform supports transparent reporting by presenting both methodology details and analysis results in a strictly structured reporting file, following the guideline checklist with minimal manual input needed. The generated reporting file can be published together with a developed prediction model, to allow thorough interrogation and external validation, as well as online application for prospective cases. We demonstrated the utilities of ReProMSig by development of prognostic molecular signatures for stage II and III colorectal cancer respectively, in comparison with a published signature reproduced by ReProMSig. Together, ReProMSig provides an integrated framework for development, evaluation and application of prognostic redictive biomarkers for cancer in a more transparent and reproducible way, which would be a useful resource for health care professionals and biomedical researchers.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 04-2013
Abstract: In iduals with adenocarcinoma of the ulla of Vater demonstrate a broad range of outcomes, presumably because these cancers may arise from any one of the three epithelia that converge at that location. This variability poses challenges for clinical decision making and the development of novel therapeutic strategies. We assessed the potential clinical utility of histomolecular phenotypes defined using a combination of histopathology and protein expression (CDX2 and MUC1) in 208 patients from three independent cohorts who underwent surgical resection for adenocarcinoma of the ulla of Vater. Histologic subtype and CDX2 and MUC1 expression were significant prognostic variables. Patients with a histomolecular pancreaticobiliary phenotype (CDX2 negative, MUC1 positive) segregated into a poor prognostic group in the training (hazard ratio [HR], 3.34 95% CI, 1.69 to 6.62 P .001) and both validation cohorts (HR, 5.65 95% CI, 2.77 to 11.5 P .001 and HR, 2.78 95% CI, 1.25 to 7.17 P = .0119) compared with histomolecular nonpancreaticobiliary carcinomas. Further stratification by lymph node (LN) status defined three clinically relevant subgroups: one, patients with histomolecular nonpancreaticobiliary (intestinal) carcinoma without LN metastases who had an excellent prognosis two, those with histomolecular pancreaticobiliary carcinoma with LN metastases who had a poor outcome and three, the remainder of patients (nonpancreaticobiliary, LN positive or pancreaticobiliary, LN negative) who had an intermediate outcome. Histopathologic and molecular criteria combine to define clinically relevant histomolecular phenotypes of adenocarcinoma of the ulla of Vater and potentially represent distinct diseases with significant implications for current therapeutic strategies, the ability to interpret past clinical trials, and future trial design.
Publisher: Springer Science and Business Media LLC
Date: 07-06-2019
DOI: 10.1038/S41467-019-10513-5
Abstract: Deterioration of biomolecules in clinical tissues is an inevitable pre-analytical process, which affects molecular measurements and thus potentially confounds conclusions from cohort analyses. Here, we investigate the degradation of mRNA and protein in 68 pairs of adjacent prostate tissue s les using RNA-Seq and SWATH mass spectrometry, respectively. To objectively quantify the extent of protein degradation, we develop a numerical score, the Proteome Integrity Number (PIN), that faithfully measures the degree of protein degradation. Our results indicate that protein degradation only affects 5.9% of the s les tested and shows negligible correlation with mRNA degradation in the adjacent s les. These findings are confirmed by independent analyses on additional clinical s le cohorts and across different mass spectrometric methods. Overall, the data show that the majority of s les tested are not compromised by protein degradation, and establish the PIN score as a generic and accurate indicator of s le quality for proteomic analyses.
Publisher: Springer Science and Business Media LLC
Date: 06-12-2022
DOI: 10.1186/S13059-022-02821-9
Abstract: Despite having been extensively studied, it remains largely unclear why humans bear a particularly high risk of cancer. The antagonistic pleiotropy hypothesis predicts that primate-specific genes (PSGs) tend to promote tumorigenesis, while the molecular atavism hypothesis predicts that PSGs involved in tumors may represent recently derived duplicates of unicellular genes. However, these predictions have not been tested. By taking advantage of pan-cancer genomic data, we find the upregulation of PSGs across 13 cancer types, which is facilitated by copy-number gain and promoter hypomethylation. Meta-analyses indicate that upregulated PSGs (uPSGs) tend to promote tumorigenesis and to play cell cycle-related roles. The cell cycle-related uPSGs predominantly represent derived duplicates of unicellular genes. We prioritize 15 uPSGs and perform an in-depth analysis of one unicellular gene-derived duplicate involved in the cell cycle, DDX11 . Genome-wide screening data and knockdown experiments demonstrate that DDX11 is broadly essential across cancer cell lines. Importantly, non-neutral amino acid substitution patterns and increased expression indicate that DDX11 has been under positive selection. Finally, we find that cell cycle-related uPSGs are also preferentially upregulated in the highly proliferative embryonic cerebrum. Consistent with the predictions of the atavism and antagonistic pleiotropy hypotheses, primate-specific genes, especially those PSGs derived from cell cycle-related genes that emerged in unicellular ancestors, contribute to the early proliferation of the human cerebrum at the cost of hitchhiking by similarly highly proliferative cancer cells.
Publisher: Springer Science and Business Media LLC
Date: 29-01-2016
DOI: 10.1038/NRC.2015.18
Abstract: Over the past decade, rapid advances in genomics, proteomics and functional genomics technologies that enable in-depth interrogation of cancer genomes and proteomes and high-throughput analysis of gene function have enabled characterization of the kinome 'at large' in human cancers, providing crucial insights into how members of the protein kinase superfamily are dysregulated in malignancy, the context-dependent functional role of specific kinases in cancer and how kinome remodelling modulates sensitivity to anticancer drugs. The power of these complementary approaches, and the insights gained from them, form the basis of this Analysis article.
Publisher: Oxford University Press (OUP)
Date: 2006
DOI: 10.1093/NAR/GKJ113
Publisher: Oxford University Press (OUP)
Date: 27-06-2011
DOI: 10.1093/NAR/GKR483
Publisher: Springer Science and Business Media LLC
Date: 09-09-2014
Publisher: Rockefeller University Press
Date: 29-06-2015
DOI: 10.1084/JEM.20150218
Abstract: The nuclear factor κB (NF-κB) pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic β cell dysfunction in the metabolic syndrome. Whereas canonical NF-κB signaling is well studied, there is little information on the ergent noncanonical NF-κB pathway in the context of pancreatic islet dysfunction. Here, we demonstrate that pharmacological activation of the noncanonical NF-κB–inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. We identify NIK as a critical negative regulator of β cell function, as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of noncanonical NF-κB components p100 to p52, and accumulation of RelB. TNF and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive β cell–intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the noncanonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to β cell failure. These studies reveal that NIK contributes a central mechanism for β cell failure in diet-induced obesity.
Publisher: American Association for Cancer Research (AACR)
Date: 15-07-2013
DOI: 10.1158/0008-5472.CAN-13-0529
Abstract: Metastasis, the leading cause of cancer death, requires tumor cell intravasation, migration through the bloodstream, arrest within capillaries, and extravasation to invade distant tissues. Few mechanistic details have been reported thus far regarding the extravasation process or re-entry of circulating tumor cells at metastatic sites. Here, we show that neuropilin-2 (NRP-2), a multifunctional nonkinase receptor for semaphorins, vascular endothelial growth factor (VEGF), and other growth factors, expressed on cancer cells interacts with α5 integrin on endothelial cells to mediate vascular extravasation and metastasis in zebrafish and murine xenograft models of clear cell renal cell carcinoma (RCC) and pancreatic adenocarcinoma. In tissue from patients with RCC, NRP-2 expression is positively correlated with tumor grade and is highest in metastatic tumors. In a prospectively acquired cohort of patients with pancreatic cancer, high NRP-2 expression cosegregated with poor prognosis. Through biochemical approaches as well as Atomic Force Microscopy (AFM), we describe a unique mechanism through which NRP-2 expressed on cancer cells interacts with α5 integrin on endothelial cells to mediate vascular adhesion and extravasation. Taken together, our studies reveal a clinically significant role of NRP-2 in cancer cell extravasation and promotion of metastasis. Cancer Res 73(14) 4579–90. ©2013 AACR.
Publisher: Proceedings of the National Academy of Sciences
Date: 26-09-2022
Abstract: β-Arrestin 1 (ARRB1) has been recognized as a multifunctional adaptor protein in the last decade, beyond its original role in desensitizing G protein-coupled receptor signaling. Here, we identify that ARRB1 plays essential roles in mediating gastric cancer (GC) cell metabolism and proliferation, by combining cohort analysis and functional investigation using patient-derived preclinical models. Overexpression of ARRB1 was associated with poor outcome of GC patients and knockdown of ARRB1 impaired cell proliferation both ex vivo and in vivo. Intriguingly, ARRB1 depicted erse subcellular localizations during a passage of organoid cultures (7 d) to exert dual functions. Further analysis revealed that nuclear ARRB1 binds with transcription factor E2F1 triggering up-regulation of proliferative genes, while cytoplasmic ARRB1 modulates metabolic flux by binding with the pyruvate kinase M2 isoform (PKM2) and hindering PKM2 tetramerization, which reduces pyruvate kinase activity and leads to cellular metabolism shifts from oxidative phosphorylation to aerobic glycolysis. As ARRB1 localization was shown mostly in the cytoplasm in human GC s les, therapeutic potential of the ARRB1–PKM2 axis was tested, and we found tumor proliferation could be attenuated by the PKM2 activator DASA-58, especially in ARRB1 high organoids. Together, the data in our study highlight a spatiotemporally dependent role of ARRB1 in mediating GC cell metabolism and proliferation and implies reactivating PKM2 may be a promising therapeutic strategy in a subset of GC patients.
Publisher: Elsevier BV
Date: 08-2016
Publisher: Springer Science and Business Media LLC
Date: 2013
DOI: 10.1186/GM482
Publisher: Springer Science and Business Media LLC
Date: 17-01-2019
DOI: 10.1038/S41467-018-08154-1
Abstract: Despite significant progress, our understanding of how specific oncogenes transform cells is still limited and likely underestimates the complexity of downstream signalling events. To address this gap, we use mass spectrometry-based chemical proteomics to characterize the global impact of an oncogene on the expressed kinome, and then functionally annotate the regulated kinases. As an ex le, we identify 63 protein kinases exhibiting altered expression and/or phosphorylation in Src-transformed mammary epithelial cells. An integrated siRNA screen identifies nine kinases, including SGK1, as being essential for Src-induced transformation. Accordingly, we find that Src positively regulates SGK1 expression in triple negative breast cancer cells, which exhibit a prominent signalling network governed by Src family kinases. Furthermore, combined inhibition of Src and SGK1 reduces colony formation and xenograft growth more effectively than either treatment alone. Therefore, this approach not only provides mechanistic insights into oncogenic transformation but also aids the design of improved therapeutic strategies.
Publisher: BMJ
Date: 15-10-2016
DOI: 10.1136/JMEDGENET-2015-103411
Abstract: High-risk human papillomavirus (hr-HPV) has been implicated in a subset of patients with oesophageal adenocarcinoma (OAC). We therefore hypothesised that HPV associated OAC may have distinct genomic aberrations compared with viral negative oesophageal cancer. Whole exome sequencing was performed to explore the mutational landscape and potential molecular signature of HPV-positive versus HPV-negative OAC. Four hr-HPV-positive and 8 HPV-negative treatment-naive fresh-frozen OAC tissue specimens and matched normal tissue were analysed to identify somatic genomic mutations. Data were subjected to cancer driver gene identification and pathway analysis. The HPV-positive cohort harboured approximately 50% less non-silent somatic mutations than the virus-negative patients with oesophageal cancer (1.31 mutations/Mb vs 2.56 mutations/Mb, p=0.048). TP53 aberrations were absent in the HPV-positive OAC group whereas 50% of the HPV-negative patients with OAC exhibited TP53 mutations. HPV-negative cancers were enriched with non-silent mutations in cancer driver genes, but not HPV-positive tumours. Enriched A>C transversions at adenine-adenine (AA) dinucleotide was observed in 5/7 Siewert class I OAC s les but none (0/5) in Siewert class II tumours (p=0.027). These findings demonstrate distinct genomic differences between HPV-positive and HPV-negative OACs indicating different biological mechanisms of tumour formation.
Publisher: Elsevier BV
Date: 04-2020
Publisher: Springer Science and Business Media LLC
Date: 14-12-2008
DOI: 10.1038/NMETH.1282
Abstract: There is an increasing demand for network analysis of protein-protein interactions (PPIs). We introduce a web-based protein interaction network analysis platform (PINA), which integrates PPI data from six databases and provides network construction, filtering, analysis and visualization tools. We demonstrated the advantages of PINA by analyzing two human PPI networks our results suggested a link between LKB1 and TGFbeta signaling, and revealed possible competitive interactors of p53 and c-Jun.
Publisher: American Association for Cancer Research (AACR)
Date: 14-08-2017
DOI: 10.1158/0008-5472.CAN-16-2550
Abstract: Despite intensive multimodal treatment of sarcomas, a heterogeneous group of malignant tumors arising from connective tissue, survival remains poor. Candidate-based targeted treatments have demonstrated limited clinical success, urging an unbiased and comprehensive analysis of oncogenic signaling networks to reveal therapeutic targets and personalized treatment strategies. Here we applied mass spectrometry–based phosphoproteomic profiling to the largest and most heterogeneous set of sarcoma cell lines characterized to date and identified novel tyrosine phosphorylation patterns, enhanced tyrosine kinases in specific subtypes, and potential driver kinases. ALK was identified as a novel driver in the Aska-SS synovial sarcoma (SS) cell line via expression of an ALK variant with a large extracellular domain deletion (ALKΔ2–17). Functional ALK dependency was confirmed in vitro and in vivo with selective inhibitors. Importantly, ALK immunopositivity was detected in 6 of 43 (14%) of SS patient specimens, one of which exhibited an ALK rearrangement. High PDGFRα phosphorylation also characterized SS cell lines, which was accompanied by enhanced MET activation in Yamato-SS cells. Although Yamato-SS cells were sensitive to crizotinib (ALK/MET-inhibitor) but not pazopanib (VEGFR/PDGFR-inhibitor) monotherapy in vitro, synergistic effects were observed upon drug combination. In vivo, both drugs were in idually effective, with pazopanib efficacy likely attributable to reduced angiogenesis. MET or PDGFRα expression was detected in 58% and 84% of SS patients, respectively, with coexpression in 56%. Consequently, our integrated approach has led to the identification of ALK and MET as promising therapeutic targets in SS. Cancer Res 77(16) 4279–92. ©2017 AACR.
Publisher: Elsevier BV
Date: 2023
Publisher: American Chemical Society (ACS)
Date: 03-12-2014
DOI: 10.1021/JP509678G
Abstract: In this work we report phase equilibrium measurements on the system (methane + carbon dioxide + water) carried out with a high-pressure quasi-static-analytical apparatus. The measurements have been made under conditions of two-phase vapor-liquid equilibrium, three-phase vapor-liquid-liquid equilibrium (VLLE), and four-phase vapor-liquid-liquid-hydrate equilibrium. The compositions of three coexisting fluid phases have been obtained along eight isotherms at temperatures from (285.15 to 303.5) K and at pressures up to either the upper critical end point (UCEP) or up to the hydrate formation locus. Compositions of coexisting vapor and liquid phases have been obtained along three isotherms at temperatures from (323.15 to 423.15) K and pressures up to 20 MPa. The quadruple curve, along which hydrates coexist with the three fluid phases, was also measured along its entire length. The VLLE data obtained for this mixture have been compared with the predictions of the statistical associating fluid theory for potentials of variable range (SAFT-VR), implemented with the square-well potential and using parameters fitted to pure-component and binary-mixture data. Specifically, we used the SAFT-VR parameters reported by Mı́guez and co-workers [Mı́guez, J. M. dos Ramos, M. C. Piñeiro, M. M. Blas, F. J. J. Phys. Chem. B 2011, 115, 9604]. The pressure along the quadruple curve was compared with the predictions of two different thermodynamic models. Furthermore, a detailed study of the ternary mixtures was carried out based on comparison with available ternary data of the type (CO2 + n-alkane + water) and available data for the constituent binary subsystems. In this way, we analyzed the observed effects on the solubility when the n-alkane component was changed or a third component was added.
Publisher: Oxford University Press (OUP)
Date: 25-05-2020
DOI: 10.1093/NAR/GKAA423
Abstract: Recent large-scale multi-omics studies resulted in quick accumulation of an overwhelming amount of cancer-related data, which provides an unprecedented resource to interrogate erse questions. While certain existing web servers are valuable and widely used, analysis and visualization functions with regard to re-investigation of these data at cohort level are not adequately addressed. Here, we present CVCDAP, a web-based platform to deliver an interactive and customizable toolbox off the shelf for cohort-level analysis of TCGA and CPTAC public datasets, as well as user uploaded datasets. CVCDAP allows flexible selection of patients sharing common molecular and/or clinical characteristics across multiple studies as a virtual cohort, and provides dozens of built-in customizable tools for seamless genomic, transcriptomic, proteomic and clinical analysis of a single virtual cohort, as well as, to compare two virtual cohorts with relevance. The flexibility and analytic competence of CVCDAP empower experimental and clinical researchers to identify new molecular mechanisms and develop potential therapeutic approaches, by building and analyzing virtual cohorts for their subject of interests. We demonstrate that CVCDAP can conveniently reproduce published findings and reveal novel insights by two applications. The CVCDAP web server is freely available at vcdap/.
No related grants have been discovered for Jianmin Wu.