Laura Beretta

University of Texas MD Anderson Cancer Center, Houston, Texas, United States

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Publications (69)439.83 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Chronic Hepatitis B (HB) is the main risk factor for chronic liver disease (CLD) and hepatocellular carcinoma (HCC) in many low-resource countries, where diagnosis is constrained by lack of clinical, histopathological and biomarker resources. We have used proteomics to detect plasma biomarkers that outperform α-Fetoprotein (AFP), the most widely used biomarker for HCC diagnosis in low-resource contexts. Deep plasma proteome analysis was performed in HCC patients, patients with chronic liver disease (CLD) and in HB-carrier controls from Thailand (South-East Asia) and The Gambia (West-Africa). Mass spectrometry profiling identified Latent-Transforming Growth Factor β Binding-Protein 2 (LTBP2) and Osteopontin (OPN) as being significantly elevated in HCC versus CLD and controls. These two proteins were further analysed by ELISA in a total of 684 plasma samples, including 183 HCC, 274 CLD and 227 asymptomatic controls. When combined, LTBP2 and OPN showed an area under the receiver operating curve (ROC) of 0.85 in distinguishing HCC from CLD in subjects with α-Fetoprotein (AFP) < 20 ng/mL. In a prospective cohort of 115 CLD patients from Korea, increased plasma levels of LTBP2 and/or OPN were detected in plasma collected over 2 years prior to diagnosis in 21 subjects who developed HCC. Thus, the combination of LTBP2 and OPN outperformed AFP for diagnosis and prediction of HCC and may therefore improve biomarker-based detection of HBV-related HCC. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 05/2014; · 6.20 Impact Factor
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    ABSTRACT: Non-alcoholic steatohepatitis (NASH) is a common pre-neoplastic condition of hepatocellular carcinoma (HCC). Mice with hepatocytic deletion of Pten develop NASH and HCC later in life. This model is highly valuable for studies aimed at identifying the molecular mechanism by which metabolic disorders contribute to tumor development. We applied proteomic and lipidomic profiling approaches to Pten null NASH liver and tumors. Circulating fatty acid composition was also characterized in these mice. The relevance to human NASH and HCC was further validated. This integrative proteomic and lipidomic study from mouse to human and from liver to blood, identified the following disease signatures: 1- an HCC signature: upregulated hepatic scd1/scd2, fads2 and acsl5:acsl1 ratio, elevated vaccenic and erucic acids and reduced margaric and linoleic acids in both liver and plasma; 2- a NASH signature that correlates with tumor burden: upregulated hepatic elovl6, elevated oleic, adrenic and osbond acids and reduced cervonic acid in liver and plasma; and 3- a NASH signature: reduced hepatic and circulating lignoceric and eicosapentaenoic acids. Altogether, these results demonstrate the role of lipid-modifying enzymes converting SFAs to MUFAs in HCC and the importance of an increased ratio of long chain n6-PUFAs over n3-PUFAs in NASH and HCC risk. They also highlight the relevance of the Pten null model for studies related to NASH and HCC and demonstrate that circulating lipid metabolome provides a direct read of lipid changes in the liver. Most importantly, novel candidate targets for HCC diagnosis, therapy, risk assessment and prevention were identified.
    Cancer Research 06/2013; · 9.28 Impact Factor
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    ABSTRACT: During the 10th HUPO Annual World Congress held in Geneva (Switzerland) from 4th to 7th September, a workshop on Human Liver Proteome Project (HLPP) Initiative took place. Four research groups presented their latest results from different ongoing projects. Later on, during the HLPP executive members' meeting, the status of current projects and the next possible steps to be taken were discussed.
    Proteomics 11/2011; 12(1):5-8. · 4.43 Impact Factor
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    ABSTRACT: The aim of this study was to identify a biomarker that could improve alpha-fetoprotein (AFP) performance in hepatocellular carcinoma (HCC) surveillance among patients with cirrhosis. We performed proteomic profiling of plasma from patients with cirrhosis or HCC and validated selected candidate HCC biomarkers in two geographically distinct cohorts to include HCC of different etiologies. Mass spectrometry profiling of highly fractionated plasma from 18 cirrhosis and 17 HCC patients identified osteopontin (OPN) as significantly up-regulated in HCC cases, compared to cirrhosis controls. OPN levels were subsequently measured in 312 plasma samples collected from 131 HCC patients, 76 cirrhosis patients, 52 chronic hepatitis C (CHC) and B (CHB) patients, and 53 healthy controls in two independent cohorts. OPN plasma levels were significantly elevated in HCC patients, compared to cirrhosis, CHC, CHB, or healthy controls, in both cohorts. OPN alone or in combination with AFP had significantly better area under the receiver operating characteristic curve, compared to AFP, in comparing cirrhosis and HCC in both cohorts. OPN overall performance remained higher than AFP in comparing cirrhosis and the following HCC groups: HCV-related HCC, HBV-associated HCC, and early HCC. OPN also had a good sensitivity in AFP-negative HCC. In a pilot prospective study including 22 patients who developed HCC during follow-up, OPN was already elevated 1 year before diagnosis. CONCLUSION: OPN was more sensitive than AFP for the diagnosis of HCC in all studied HCC groups. In addition, OPN performance remained intact in samples collected 1 year before diagnosis.
    Hepatology 09/2011; 55(2):483-90. · 12.00 Impact Factor
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    ABSTRACT: After the successful completion of the Human Genome Project, the Human Proteome Organization has recently officially launched a global Human Proteome Project (HPP), which is designed to map the entire human protein set. Given the lack of protein-level evidence for about 30% of the estimated 20,300 protein-coding genes, a systematic global effort will be necessary to achieve this goal with respect to protein abundance, distribution, subcellular localization, interaction with other biomolecules, and functions at specific time points. As a general experimental strategy, HPP research groups will use the three working pillars for HPP: mass spectrometry, antibody capture, and bioinformatics tools and knowledge bases. The HPP participants will take advantage of the output and cross-analyses from the ongoing Human Proteome Organization initiatives and a chromosome-centric protein mapping strategy, termed C-HPP, with which many national teams are currently engaged. In addition, numerous biologically driven and disease-oriented projects will be stimulated and facilitated by the HPP. Timely planning with proper governance of HPP will deliver a protein parts list, reagents, and tools for protein studies and analyses, and a stronger basis for personalized medicine. The Human Proteome Organization urges each national research funding agency and the scientific community at large to identify their preferred pathways to participate in aspects of this highly promising project in a HPP consortium of funders and investigators.
    Molecular &amp Cellular Proteomics 07/2011; 10(7):M111.009993. · 7.25 Impact Factor
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    ABSTRACT: We are reporting qualitative and quantitative changes of the extracellular matrix (ECM) and associated receptor proteomes, occurring during the transition from liver fibrosis and steatohepatitis to hepatocellular carcinoma (HCC). We compared two mouse models relevant to human HCC: PDGFC transgenic (Tg) and Pten null mice, models of disease progression from fibrosis and steatohepatitis to HCC. Using mass spectrometry, we identified in the liver of both models proteins for 26 collagen-encoding genes, providing the first evidence of expression at the protein level for 16 collagens. We also identified post-transcriptional protein variants for six collagens and lysine hydroxylation modifications for 14 collagens. Tumor-associated collagen proteomes were similar in both models with increased expression of collagens type IV, VI, VII, X, XIV, XV, XVI, and XVIII. Splice variants for Col4a2, Col6a2, Col6a3 were co-upregulated while only the short form of Col18a1 increased in the tumors. We also identified tumor specific increases of nidogen 1, decorin, perlecan, and of six laminin subunits. The changes in these non-collagenous ECM proteins were similar in both models with the exception of laminin β3, detected specifically in the Pten null tumors. Pdgfa and Pdgfc mRNA expression was increased in the Pten null liver, a possible mechanism for the similarity in ECM composition observed in the tumors of both models. In contrast and besides the strong up-regulation of integrin α5 protein observed in the liver tumors of both models, the expression of the six other integrins identified was specific to each model, with integrins α2b, α3, α6, and β1 up-regulated in Pten null tumors and integrins α8 and β5 up-regulated in the PDGFC Tg tumors. In conclusion, HCC-associated ECM proteins and ECM-integrin networks, common or specific to HCC subtypes, were identified, providing a unique foundation to using ECM composition for HCC classification, diagnosis, prevention, or treatment.
    PLoS Genetics 06/2011; 7(6):e1002147. · 8.52 Impact Factor
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    ABSTRACT: After successful completion of the Human Genome Project (HGP), HUPO has recently officially launched a global Human Proteome Project (HPP) which is designed to map the entire human protein set. Given the presence of about 30% undisclosed proteins out of 20,300 protein gene products, a systematic global effort is necessary to achieve this goal with respect to protein abundance, distribution, subcellular localization, interaction with other biomolecules, and functions at specific time points. As a general experimental strategy, HPP groups employ the three working pillars for HPP: mass spectrometry, antibody capture, and bioinformatics tools and knowledge base. The HPP participants will take advantage of the output and cross-analyses from the ongoing HUPO initiatives and a chromosome-based protein mapping strategy, termed C-HPP with many national teams currently engaged. In addition, numerous biologically-driven projects will be stimulated and facilitated by the HPP. Timely planning with proper governance of HPP will deliver a protein parts list, reagents and tools for protein studies and analyses, and a stronger basis for personalized medicine. HUPO urges each national research funding agency and the scientific community at large to identify their preferred pathways to participate in aspects of this highly promising project in a HPP consortium of funders and investigators.
    Molecular &amp Cellular Proteomics 04/2011; · 7.25 Impact Factor
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    ABSTRACT: MicroRNAs miR-122, miR-34a, miR-16 and miR-21 are commonly deregulated in liver fibrosis and hepatocellular carcinoma. This study examined whether circulating levels of these miRNAs correlate with hepatic histological disease severity in patients with chronic hepatitis C infection (CHC) or non-alcoholic fatty-liver disease (NAFLD) and can potentially serve as circulating markers for disease stage assessment. We first used an in vitro model of hepatitis C virus (HCV) infection to measure the extracellular levels of these four miRNAs. Whereas miR-21 extracellular levels were unchanged, extracellular levels of miR-122, miR-34a and to a lesser extent miR-16, steadily increased during the course of HCV infection, independently of viral replication and production. Similarly, in CHC patients, serum levels of miR-122, miR-34a and miR-16 were significantly higher than in control individuals, while miR-21 levels were unchanged. There was no correlation between the serum levels of any of these microRNAs and HCV viral loads. In contrast, miR-122 and miR-34a levels positively correlated with disease severity. Identical results were obtained in an independent cohort of CHC patients. We extended the study to patients with NAFLD. As observed in CHC patients, serum levels of miR-122, miR-34a and miR-16 were significantly higher in NAFLD patients than in controls, while miR-21 levels were unchanged. Again, miR-122 and miR-34a levels positively correlated with disease severity from simple steatosis to steatohepatitis. In both CHC and NAFLD patient groups, serum levels of miR-122 and miR-34a correlated with liver enzymes levels, fibrosis stage and inflammation activity. miR-122 levels also correlated with serum lipids in NAFLD patients. CONCLUSION: Serum levels of miR-34a and miR-122 may represent novel, noninvasive biomarkers of diagnosis and histological disease severity in patients with CHC or NAFLD.
    PLoS ONE 01/2011; 6(8):e23937. · 3.53 Impact Factor
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    ABSTRACT: The Human Liver Proteome Project (HLPP) was formally launched by HUPO in 2002. The 11th HLPP Workshop was held on September 26th, 2009 during the 8th HUPO World Congress in Toronto, Canada. The representative progresses were presented from four groups. Subsequently, the workshop ended with a lively discussion on four topics related to the project as well as other initiatives.
    Proteomics 09/2010; 10(17):3058-61. · 4.43 Impact Factor
  • Laura Beretta
    PROTEOMICS - CLINICAL APPLICATIONS 04/2010; 4(4):359-61. · 1.81 Impact Factor
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    Laura Beretta
    Journal of Proteome Research 02/2010; 9(2):637-8. · 5.06 Impact Factor
  • Laura Beretta
    Proteomics 11/2009; 9(21):4830-3. · 4.43 Impact Factor
  • Laura Beretta
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    ABSTRACT: Translational control is an important but relatively unappreciated mechanism that regulates levels of protein products. In addition to a global translational control that regulates the cell's response to external stimuli such as growth factors, cytokines, stress, and viral infections, selective translational control has recently been demonstrated to affect many genes related to growth and apoptotic processes. Translational infidelity has recently been suggested as a new mechanism of T cell dysregulation in SLE. This review discusses current data on translational control of T cell biology and the central aspect of translational control in the signalling pathway leading to T cell proliferation, apoptotic response, and cytokine production. The utility for global analysis by genomics to study translational control of T cell gene expression is also discussed.
    International Reviews Of Immunology 08/2009; 23(3-4):347-63. · 5.73 Impact Factor
  • Laura Beretta
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    ABSTRACT: The extraordinary developments made in the past decade in proteomic technologies, in particular in mass spectrometry, have enabled investigators to consider designing studies to search for diagnostic and therapeutic biomarkers by scanning complex proteome samples. We developed a method based on extensive fractionation of intact proteins, to comprehensively and quantitatively profile the liver and plasma proteomes in health and disease. We have applied this method to samples collected from patients with early hepatocellular carcinoma (HCC) and from patients with liver cirrhosis as well as to samples collected from three mouse models of HCC. This method allowed for the identification of proteins that differ in expression levels in liver tissue or in plasma with disease progression from liver fibrosis, cirrhosis or steatohepatitis to HCC. The comparative analysis of the liver and plasma proteomes generated from human and mouse specimens, constitutes a novel and powerful strategy for HCC biomarker discovery.
    Cancer letters 03/2009; 286(1):134-9. · 5.02 Impact Factor
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    ABSTRACT: There is growing evidence that virus particles contain host cell proteins. These proteins may provide viruses with means to evade the immune system or with mechanisms for cell entry and release. A proteomic analysis performed on highly purified hepatitis C virus (HCV) J6/JFH virions identified the heat shock cognate protein 70 (HSC70) as part of the viral particles. These results were further validated via immunogold electron microscopy. The HSC70 interaction HPD motif was found present on the E2 envelope of the J6/JFH strain, as well as in over 50% of genotype 2 clinical HCV isolates. In addition, HSC70 was found associated with viral particles from an HCV genotype 2a-infected patient. Preincubation of HCV particles with anti-HSC70 antibodies decreased viral infectivity. Within infected cells, colocalization of HSC70 with the HCV core and E2 proteins was observed around lipid droplets. Reduction of HSC70 expression using an RNA interference approach decreased the volume of lipid droplets as well as viral release without affecting HCV replication levels. Conclusion: These results suggest that HSC70 modulates HCV infectivity and lipid droplet-dependent virus release.
    Hepatology 02/2009; 49(6):1798-809. · 12.00 Impact Factor
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    ABSTRACT: Hepatocellular carcinoma (HCC) is an aggressive liver cancer but clinically validated biomarkers that can predict natural history of malignant progression are lacking. The present study explored the proteome-wide patterns of HCC to identify biomarker signature that could distinguish cancerous and nonmalignant liver tissues. A retrospective cohort of 80 HBV-associated HCC was included and both the tumor and adjacent nontumor tissues were subjected to proteome-wide expression profiling by 2-DE method. The subjects were randomly divided into the training (n = 55) and validation (n = 25) subsets, and the data analyzed by classification-and-regression tree algorithm. Protein markers were characterized by MALDI-ToF/MS and confirmed by immunohistochemistry, Western blotting and qPCR assays. Proteomic expression signature composed of six biomarkers (haptoglobin, cytochrome b5, progesterone receptor membrane component 1, heat shock 27 kDa protein 1, lysosomal proteinase cathepsin B, keratin I) was developed as a classifier model for predicting HCC. We further evaluated the model using both leave-one-out procedure and independent validation, and the overall sensitivity and specificity for HCC both are 92.5%, respectively. Clinical correlation analysis revealed that these biomarkers were significantly associated with serum AFP, total protein levels and the Ishak’s score. The described model using biomarker signatures could accurately distinguish HCC from nonmalignant tissues, which may also provide hints on how normal hepatocytes are transformed to malignant state during tumor progression.Keywords: hepatocellular carcinoma; tumor markers; proteomics; diagnosis and prognosis
    Journal of Proteome Research 01/2009; 8(3). · 5.06 Impact Factor
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    ABSTRACT: We investigated the role of two repressors of translation initiation in granulocytic differentiation using mice with a null mutation in the 4E-BP1 gene or with a null mutation in the 4E-BP2 gene. We show that 4E-BP1(-/-) and 4E-BP2(-/-) mice exhibit an increased number of immature granulocytic precursors, associated with a decreased number of mature granulocytic elements compared with wild-type mice, which is suggestive of an impaired granulocytic differentiation. Clonogenetic analyses revealed a reduced number of granulocytic colonies and concomitant increase in granulo-monocytic colonies in 4E-BP(-/-) mice. Finally, a slight expansion of monocytic cells was observed in the 4E-BP2(-/-) mice. In contrast, we did not observe any significant difference in thymocyte maturation in these mice. These results, together with the fact that 4E-BPs are markedly induced during granulo-monocytic differentiation of myeloid cells in vitro, highlight the pivotal role of 4E-BP1 and 4E-BP2 in the early phases of myelopoiesis. These results represent the first in vivo evidence of the involvement of translation in the early phases of granulo-monocytic differentiation and further extend the role of translation in haematopoietic differentiation.
    Immunology 11/2008; 128(1 Suppl):e376-84. · 3.71 Impact Factor
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    ABSTRACT: The Human Liver Proteome Project is one of the Human Proteome Initiatives launched by Human Proteome Organization (HUPO). Major achievements of the project have been obtained under the efforts of international collaboration with all the participants since it was formally proposed in 2002. Its updated progresses were presented in the latest workshop held in conjunction with the sixth HUPO World Congress in October, 2007, Seoul, Korea. Furthermore, four topics related to the project as well as other initiatives were lively discussed among all the attendees.
    Proteomics 10/2008; 8(17):3420-3. · 4.43 Impact Factor
  • A. Plymoth, P. Hainaut, L. Beretta
    EJC Supplements 07/2008; 6(9):195-196. · 2.71 Impact Factor
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    ABSTRACT: We report a comprehensive and quantitative analysis of the mouse liver and plasma proteomes. The method used is based on extensive fractionation of intact proteins, further separation of proteins based on their abundance and size, and high-accuracy mass spectrometry. This analysis reached a depth in proteomic profiling not reported to date for a mammalian tissue or a biological fluid, with 7099 and 4727 proteins identified with high confidence in the liver and in the corresponding plasma, respectively. This method allowed for the identification in both compartments of low-abundance proteins such as cytokines, chemokines, and receptors and for the detection in plasma of proteins in the pg/mL concentration range. This method also allowed for semiquantitation of all identified proteins. The calculated abundance scores correlated with the abundance of the corresponding transcripts for the large majority of the proteins identified in the liver. Finally, comparison of the liver and plasma datasets demonstrated that a significant number of proteins identified in the liver can be detected in plasma. These included proteins involved in complement and coagulation, in fatty acid, purine and pyruvate metabolism, in gluconeogenesis and glycolysis, in protein ubiquitination, and in insulin, interleukin-4, epidermal growth factor, and platelet-derived growth factor signaling. CONCLUSION: This in-depth analysis of the mouse liver and corresponding plasma proteomes provides a strong basis for investigations of liver pathobiology and biology that employ mouse models of hepatic diseases in an effort to better understand, diagnose, treat, and prevent human hepatic diseases.
    Hepatology 04/2008; 47(3):1043-51. · 12.00 Impact Factor

Publication Stats

2k Citations
439.83 Total Impact Points

Institutions

  • 2014
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
  • 2004–2013
    • Fred Hutchinson Cancer Research Center
      • • Molecular Diagnostics Program
      • • Division of Public Health Sciences
      Seattle, Washington, United States
  • 2006–2010
    • Beijing Proteome Research Center
      Peping, Beijing, China
  • 2001–2009
    • University of Michigan
      • • Department of Microbiology and Immunology
      • • Division of Pediatric Genetics
      Ann Arbor, MI, United States
  • 1993–2006
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 1998–2001
    • Institut Curie
      Lutetia Parisorum, Île-de-France, France
  • 1993–2000
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 1993–1997
    • McGill University
      • Department of Biochemistry
      Montréal, Quebec, Canada