Distinct serum metabolomics profiles associated with malignant progression in the KrasG12D mouse model of pancreatic ductal adenocarcinoma

Joseph J. LaConti, Evagelia C. Laiakis, Deslattes D. Mays, Ivana Peran, Sung Eun Kim, Jerry W. Shay, Anna T. Riegel, Albert J. Fornace, Anton Wellstein

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths worldwide with less than a 6% 5-year survival rate. PDAC is associated with poor prognosis based on the late stage diagnosis of the disease. Current diagnostic tests lack the sensitivity and specificity to identify markers of early staging. Metabolomics has provided biomarkers for various diseases, stressors, and environmental exposures. In this study we utilized the p48-Cre/LSL-KrasG12D mouse model with age-matched wild type mice. This model shows malignant progression to PDAC analogous to the human disease stages via early and late pancreatic intra-epithelial neoplasia (PanIN) lesions. Results: Serum was collected from mice with early PanIN lesions (at 3-5 months) and with late PanIN or invasive PDAC lesions (13-16 months), as determined by histopathology. Metabolomics analysis of the serum samples was conducted through UPLC-TOFMS (Ultra Performance Liquid Chromatography coupled to Time-of-flight Mass Spectrometry). Multivariate data analysis revealed distinct metabolic patterns in serum samples collected during malignant progression towards invasive PDAC. Animals with early or late stage lesions were distinguished from their respective controls with 82.1% and 81.5% accuracy, respectively. This also held up for randomly selected subgroups in the late stage lesion group that showed less variability between animals. One of the metabolites, citrate, was validated through tandem mass spectrometry and showed increased levels in serum with disease progression. Furthermore, serum metabolite signatures from animals with early stage lesions identified controls and animals with late stage lesions with 81.5% accuracy (p<0.01) and vice-versa with 73.2% accuracy (p<0.01). Conclusions: We conclude that metabolomics analysis of serum samples can identify the presence of early and late stage pancreatic cancer.

Original languageEnglish (US)
Article number9999
JournalBMC Genomics
Volume16
Issue number1
DOIs
StatePublished - Jan 15 2015

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Metabolomics
Adenocarcinoma
Serum
Neoplasms
Delayed Diagnosis
Environmental Exposure
Tandem Mass Spectrometry
Pancreatic Neoplasms
Routine Diagnostic Tests
Citric Acid
Liquid Chromatography
Disease Progression
Cause of Death
Mass Spectrometry
Multivariate Analysis
Survival Rate
Biomarkers
Sensitivity and Specificity

ASJC Scopus subject areas

  • Biotechnology
  • Genetics

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Distinct serum metabolomics profiles associated with malignant progression in the KrasG12D mouse model of pancreatic ductal adenocarcinoma. / LaConti, Joseph J.; Laiakis, Evagelia C.; Mays, Deslattes D.; Peran, Ivana; Kim, Sung Eun; Shay, Jerry W.; Riegel, Anna T.; Fornace, Albert J.; Wellstein, Anton.

In: BMC Genomics, Vol. 16, No. 1, 9999, 15.01.2015.

Research output: Contribution to journalArticle

LaConti, Joseph J. ; Laiakis, Evagelia C. ; Mays, Deslattes D. ; Peran, Ivana ; Kim, Sung Eun ; Shay, Jerry W. ; Riegel, Anna T. ; Fornace, Albert J. ; Wellstein, Anton. / Distinct serum metabolomics profiles associated with malignant progression in the KrasG12D mouse model of pancreatic ductal adenocarcinoma. In: BMC Genomics. 2015 ; Vol. 16, No. 1.
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abstract = "Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths worldwide with less than a 6{\%} 5-year survival rate. PDAC is associated with poor prognosis based on the late stage diagnosis of the disease. Current diagnostic tests lack the sensitivity and specificity to identify markers of early staging. Metabolomics has provided biomarkers for various diseases, stressors, and environmental exposures. In this study we utilized the p48-Cre/LSL-KrasG12D mouse model with age-matched wild type mice. This model shows malignant progression to PDAC analogous to the human disease stages via early and late pancreatic intra-epithelial neoplasia (PanIN) lesions. Results: Serum was collected from mice with early PanIN lesions (at 3-5 months) and with late PanIN or invasive PDAC lesions (13-16 months), as determined by histopathology. Metabolomics analysis of the serum samples was conducted through UPLC-TOFMS (Ultra Performance Liquid Chromatography coupled to Time-of-flight Mass Spectrometry). Multivariate data analysis revealed distinct metabolic patterns in serum samples collected during malignant progression towards invasive PDAC. Animals with early or late stage lesions were distinguished from their respective controls with 82.1{\%} and 81.5{\%} accuracy, respectively. This also held up for randomly selected subgroups in the late stage lesion group that showed less variability between animals. One of the metabolites, citrate, was validated through tandem mass spectrometry and showed increased levels in serum with disease progression. Furthermore, serum metabolite signatures from animals with early stage lesions identified controls and animals with late stage lesions with 81.5{\%} accuracy (p<0.01) and vice-versa with 73.2{\%} accuracy (p<0.01). Conclusions: We conclude that metabolomics analysis of serum samples can identify the presence of early and late stage pancreatic cancer.",
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AU - LaConti, Joseph J.

AU - Laiakis, Evagelia C.

AU - Mays, Deslattes D.

AU - Peran, Ivana

AU - Kim, Sung Eun

AU - Shay, Jerry W.

AU - Riegel, Anna T.

AU - Fornace, Albert J.

AU - Wellstein, Anton

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AB - Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths worldwide with less than a 6% 5-year survival rate. PDAC is associated with poor prognosis based on the late stage diagnosis of the disease. Current diagnostic tests lack the sensitivity and specificity to identify markers of early staging. Metabolomics has provided biomarkers for various diseases, stressors, and environmental exposures. In this study we utilized the p48-Cre/LSL-KrasG12D mouse model with age-matched wild type mice. This model shows malignant progression to PDAC analogous to the human disease stages via early and late pancreatic intra-epithelial neoplasia (PanIN) lesions. Results: Serum was collected from mice with early PanIN lesions (at 3-5 months) and with late PanIN or invasive PDAC lesions (13-16 months), as determined by histopathology. Metabolomics analysis of the serum samples was conducted through UPLC-TOFMS (Ultra Performance Liquid Chromatography coupled to Time-of-flight Mass Spectrometry). Multivariate data analysis revealed distinct metabolic patterns in serum samples collected during malignant progression towards invasive PDAC. Animals with early or late stage lesions were distinguished from their respective controls with 82.1% and 81.5% accuracy, respectively. This also held up for randomly selected subgroups in the late stage lesion group that showed less variability between animals. One of the metabolites, citrate, was validated through tandem mass spectrometry and showed increased levels in serum with disease progression. Furthermore, serum metabolite signatures from animals with early stage lesions identified controls and animals with late stage lesions with 81.5% accuracy (p<0.01) and vice-versa with 73.2% accuracy (p<0.01). Conclusions: We conclude that metabolomics analysis of serum samples can identify the presence of early and late stage pancreatic cancer.

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