MALDI Imaging Mass Spectrometry for in Situ Proteomic Analysis of Preneoplastic Lesions in Pancreatic Cancer

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2012 Jul 5

PMID 22761793

Citations 15

Authors

Barbara M Gruner

Hannes Hahne

Pawel K Mazur

Marija Trajkovic-Arsic

Stefan Maier

Irene Esposito

Evdokia Kalideris

Christoph W Michalski

Jorg Kleeff

Sandra Rauser

Roland M Schmid

Bernhard Kuster

Axel Walch

Jens T Siveke

Affiliations

Soon will be listed here.

Abstract

The identification of new biomarkers for preneoplastic pancreatic lesions (PanINs, IPMNs) and early pancreatic ductal adenocarcinoma (PDAC) is crucial due to the diseases high mortality rate upon late detection. To address this task we used the novel technique of matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) on genetically engineered mouse models (GEM) of pancreatic cancer. Various GEM were analyzed with MALDI IMS to investigate the peptide/protein-expression pattern of precursor lesions in comparison to normal pancreas and PDAC with cellular resolution. Statistical analysis revealed several discriminative m/z-species between normal and diseased tissue. Intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) could be distinguished from normal pancreatic tissue and PDAC by 26 significant m/z-species. Among these m/z-species, we identified Albumin and Thymosin-beta 4 by liquid chromatography and tandem mass spectrometry (LC-MS/MS), which were further validated by immunohistochemistry, western blot, quantitative RT-PCR and ELISA in both murine and human tissue. Thymosin-beta 4 was found significantly increased in sera of mice with PanIN lesions. Upregulated PanIN expression of Albumin was accompanied by increased expression of liver-restricted genes suggesting a hepatic transdifferentiation program of preneoplastic cells. In conclusion we show that GEM of endogenous PDAC are a suitable model system for MALDI-IMS and subsequent LC-MS/MS analysis, allowing in situ analysis of small precursor lesions and identification of differentially expressed peptides and proteins.

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References

Lardon J, De Breuck S, Rooman I, Van Lommel L, Kruhoffer M, Orntoft T . Plasticity in the adult rat pancreas: transdifferentiation of exocrine to hepatocyte-like cells in primary culture. Hepatology. 2004; 39(6):1499-507. DOI: 10.1002/hep.20213. View

Kim N, Yoo W, Lee J, Kim H, Lee H, Kim Y . Formation of vitamin A lipid droplets in pancreatic stellate cells requires albumin. Gut. 2009; 58(10):1382-90. DOI: 10.1136/gut.2008.170233. View

Canto M, Goggins M, Hruban R, Petersen G, Giardiello F, Yeo C . Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study. Clin Gastroenterol Hepatol. 2006; 4(6):766-81. DOI: 10.1016/j.cgh.2006.02.005. View

Stoeckli M, Staab D, Staufenbiel M, Wiederhold K, Signor L . Molecular imaging of amyloid beta peptides in mouse brain sections using mass spectrometry. Anal Biochem. 2002; 311(1):33-9. DOI: 10.1016/s0003-2697(02)00386-x. View

Cingolani N, Shaco-Levy R, Farruggio A, Klimstra D, Rosai J . Alpha-fetoprotein production by pancreatic tumors exhibiting acinar cell differentiation: study of five cases, one arising in a mediastinal teratoma. Hum Pathol. 2000; 31(8):938-44. DOI: 10.1053/hupa.2000.9075. View

Shen C, Seckl J, Slack J, Tosh D . Glucocorticoids suppress beta-cell development and induce hepatic metaplasia in embryonic pancreas. Biochem J. 2003; 375(Pt 1):41-50. PMC: 1223676. DOI: 10.1042/bj20030140. View

Sandgren E, Luetteke N, Palmiter R, Brinster R, Lee D . Overexpression of TGF alpha in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell. 1990; 61(6):1121-35. DOI: 10.1016/0092-8674(90)90075-p. View

Walch A, Rauser S, Deininger S, Hofler H . MALDI imaging mass spectrometry for direct tissue analysis: a new frontier for molecular histology. Histochem Cell Biol. 2008; 130(3):421-34. PMC: 2522327. DOI: 10.1007/s00418-008-0469-9. View

Nakhai H, Sel S, Favor J, Mendoza-Torres L, Paulsen F, Duncker G . Ptf1a is essential for the differentiation of GABAergic and glycinergic amacrine cells and horizontal cells in the mouse retina. Development. 2007; 134(6):1151-60. DOI: 10.1242/dev.02781. View

10.

Shen C, Slack J, Tosh D . Molecular basis of transdifferentiation of pancreas to liver. Nat Cell Biol. 2001; 2(12):879-87. DOI: 10.1038/35046522. View

11.

Caprioli R . Deciphering protein molecular signatures in cancer tissues to aid in diagnosis, prognosis, and therapy. Cancer Res. 2005; 65(23):10642-5. DOI: 10.1158/0008-5472.CAN-04-3581. View

12.

Schneider G, Siveke J, Eckel F, Schmid R . Pancreatic cancer: basic and clinical aspects. Gastroenterology. 2005; 128(6):1606-25. DOI: 10.1053/j.gastro.2005.04.001. View

13.

Spurney C, Cha H, Sali A, Pandey G, Pistilli E, Guerron A . Evaluation of skeletal and cardiac muscle function after chronic administration of thymosin beta-4 in the dystrophin deficient mouse. PLoS One. 2010; 5(1):e8976. PMC: 2813286. DOI: 10.1371/journal.pone.0008976. View

14.

Chaurand P, DaGue B, Pearsall R, Threadgill D, Caprioli R . Profiling proteins from azoxymethane-induced colon tumors at the molecular level by matrix-assisted laser desorption/ionization mass spectrometry. Proteomics. 2001; 1(10):1320-6. DOI: 10.1002/1615-9861(200110)1:10<1320::AID-PROT1320>3.0.CO;2-G. View

15.

Taguchi A, Politi K, Pitteri S, Lockwood W, Faca V, Kelly-Spratt K . Lung cancer signatures in plasma based on proteome profiling of mouse tumor models. Cancer Cell. 2011; 20(3):289-99. PMC: 3406925. DOI: 10.1016/j.ccr.2011.08.007. View

16.

Schwartz S, Weil R, Thompson R, Shyr Y, Moore J, Toms S . Proteomic-based prognosis of brain tumor patients using direct-tissue matrix-assisted laser desorption ionization mass spectrometry. Cancer Res. 2005; 65(17):7674-81. DOI: 10.1158/0008-5472.CAN-04-3016. View

17.

DABEVA M, Hurston E, Shafritz D . Transcription factor and liver-specific mRNA expression in facultative epithelial progenitor cells of liver and pancreas. Am J Pathol. 1995; 147(6):1633-48. PMC: 1869941. View

18.

Hruban R, Takaori K, Klimstra D, Adsay N, Albores-Saavedra J, Biankin A . An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol. 2004; 28(8):977-87. DOI: 10.1097/01.pas.0000126675.59108.80. View

19.

Jaskolla T, Karas M, Roth U, Steinert K, Menzel C, Reihs K . Comparison between vacuum sublimed matrices and conventional dried droplet preparation in MALDI-TOF mass spectrometry. J Am Soc Mass Spectrom. 2009; 20(6):1104-14. DOI: 10.1016/j.jasms.2009.02.010. View

20.

Hingorani S, Wang L, Multani A, Combs C, Deramaudt T, Hruban R . Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 2005; 7(5):469-83. DOI: 10.1016/j.ccr.2005.04.023. View