Multi-omics integration analysis robustly predicts high-grade patient survival and identifies CPT1B effect on fatty acid metabolism in Bladder Cancer

Venkatrao Vantaku, Jianrong Dong, Chandrashekar R. Ambati, Dimuthu Perera, Sri Ramya Donepudi, Chandra Sekhar Amara, Vasanta Putluri, Shiva Shankar Ravi, Matthew J. Robertson, Danthasinghe Waduge Badrajee Piyarathna, Mariana Villanueva, Friedrich Carl Von Rundstedt, Balasubramanyam Karanam, Leomar Y. Ballester, Martha Kennedy Terris, Roni Jacob Bollag, Seth P. Lerner, Andrea B. Apolo, Hugo Villanueva, Minjae Lee & 5 others Andrew G. Sikora, Yair Lotan, Arun Sreekumar, Cristian Coarfa, Nagireddy Putluri

Research output: Contribution to journalArticle

Abstract

Purpose: The perturbation of metabolic pathways in high-grade bladder cancer has not been investigated. We aimed to identify a metabolic signature in high-grade bladder cancer by integrating unbiased metabolomics, lipidomics, and transcriptomics to predict patient survival and to discover novel therapeutic targets. Experimental Design: We performed high-resolution liquid chromatography mass spectrometry (LC-MS) and bioinformatic analysis to determine the global metabolome and lipidome in high-grade bladder cancer.Wefurther investigated the effects of impaired metabolic pathways using in vitro and in vivo models. Results: We identified 519 differential metabolites and 19 lipids that were differentially expressed between low-grade and high-grade bladder cancer using the NIST MS metabolomics compendium and lipidblast MS/MS libraries, respectively. Pathway analysis revealed a unique set of biochemical pathways that are highly deregulated in high-grade bladder cancer. Integromics analysis identified a molecular gene signature associated with poor patient survival in bladder cancer. Low expression of CPT1B in high-grade tumors was associated with low FAO and low acyl carnitine levels in high-grade bladder cancer, which were confirmed using tissue microarrays. Ectopic expression of the CPT1B in high-grade bladder cancer cells led to reduced EMT in in vitro, and reduced cell proliferation, EMT, and metastasis in vivo. Conclusions: Our study demonstrates a novel approach for the integration of metabolomics, lipidomics, and transcriptomics data, and identifies a common gene signature associated with poor survival in patients with bladder cancer. Our data also suggest that impairment of FAO due to downregulation of CPT1B plays an important role in the progression toward high-grade bladder cancer and provide potential targets for therapeutic intervention.

Original languageEnglish (US)
Pages (from-to)3689-3701
Number of pages13
JournalClinical Cancer Research
Volume25
Issue number12
DOIs
StatePublished - Jun 15 2019

Fingerprint

Urinary Bladder Neoplasms
Fatty Acids
Survival
Metabolomics
Metabolic Networks and Pathways
Metabolome
Carnitine
Computational Biology
Liquid Chromatography
Genes
Libraries
Mass Spectrometry
Research Design
Down-Regulation
Cell Proliferation
Neoplasm Metastasis
Lipids
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Multi-omics integration analysis robustly predicts high-grade patient survival and identifies CPT1B effect on fatty acid metabolism in Bladder Cancer. / Vantaku, Venkatrao; Dong, Jianrong; Ambati, Chandrashekar R.; Perera, Dimuthu; Donepudi, Sri Ramya; Amara, Chandra Sekhar; Putluri, Vasanta; Ravi, Shiva Shankar; Robertson, Matthew J.; Piyarathna, Danthasinghe Waduge Badrajee; Villanueva, Mariana; Von Rundstedt, Friedrich Carl; Karanam, Balasubramanyam; Ballester, Leomar Y.; Terris, Martha Kennedy; Bollag, Roni Jacob; Lerner, Seth P.; Apolo, Andrea B.; Villanueva, Hugo; Lee, Minjae; Sikora, Andrew G.; Lotan, Yair; Sreekumar, Arun; Coarfa, Cristian; Putluri, Nagireddy.

In: Clinical Cancer Research, Vol. 25, No. 12, 15.06.2019, p. 3689-3701.

Research output: Contribution to journalArticle

Vantaku, V, Dong, J, Ambati, CR, Perera, D, Donepudi, SR, Amara, CS, Putluri, V, Ravi, SS, Robertson, MJ, Piyarathna, DWB, Villanueva, M, Von Rundstedt, FC, Karanam, B, Ballester, LY, Terris, MK, Bollag, RJ, Lerner, SP, Apolo, AB, Villanueva, H, Lee, M, Sikora, AG, Lotan, Y, Sreekumar, A, Coarfa, C & Putluri, N 2019, 'Multi-omics integration analysis robustly predicts high-grade patient survival and identifies CPT1B effect on fatty acid metabolism in Bladder Cancer', Clinical Cancer Research, vol. 25, no. 12, pp. 3689-3701. https://doi.org/10.1158/1078-0432.CCR-18-1515
Vantaku, Venkatrao ; Dong, Jianrong ; Ambati, Chandrashekar R. ; Perera, Dimuthu ; Donepudi, Sri Ramya ; Amara, Chandra Sekhar ; Putluri, Vasanta ; Ravi, Shiva Shankar ; Robertson, Matthew J. ; Piyarathna, Danthasinghe Waduge Badrajee ; Villanueva, Mariana ; Von Rundstedt, Friedrich Carl ; Karanam, Balasubramanyam ; Ballester, Leomar Y. ; Terris, Martha Kennedy ; Bollag, Roni Jacob ; Lerner, Seth P. ; Apolo, Andrea B. ; Villanueva, Hugo ; Lee, Minjae ; Sikora, Andrew G. ; Lotan, Yair ; Sreekumar, Arun ; Coarfa, Cristian ; Putluri, Nagireddy. / Multi-omics integration analysis robustly predicts high-grade patient survival and identifies CPT1B effect on fatty acid metabolism in Bladder Cancer. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 12. pp. 3689-3701.
@article{56c2fa3c8de045ec930549329710027f,
title = "Multi-omics integration analysis robustly predicts high-grade patient survival and identifies CPT1B effect on fatty acid metabolism in Bladder Cancer",
abstract = "Purpose: The perturbation of metabolic pathways in high-grade bladder cancer has not been investigated. We aimed to identify a metabolic signature in high-grade bladder cancer by integrating unbiased metabolomics, lipidomics, and transcriptomics to predict patient survival and to discover novel therapeutic targets. Experimental Design: We performed high-resolution liquid chromatography mass spectrometry (LC-MS) and bioinformatic analysis to determine the global metabolome and lipidome in high-grade bladder cancer.Wefurther investigated the effects of impaired metabolic pathways using in vitro and in vivo models. Results: We identified 519 differential metabolites and 19 lipids that were differentially expressed between low-grade and high-grade bladder cancer using the NIST MS metabolomics compendium and lipidblast MS/MS libraries, respectively. Pathway analysis revealed a unique set of biochemical pathways that are highly deregulated in high-grade bladder cancer. Integromics analysis identified a molecular gene signature associated with poor patient survival in bladder cancer. Low expression of CPT1B in high-grade tumors was associated with low FAO and low acyl carnitine levels in high-grade bladder cancer, which were confirmed using tissue microarrays. Ectopic expression of the CPT1B in high-grade bladder cancer cells led to reduced EMT in in vitro, and reduced cell proliferation, EMT, and metastasis in vivo. Conclusions: Our study demonstrates a novel approach for the integration of metabolomics, lipidomics, and transcriptomics data, and identifies a common gene signature associated with poor survival in patients with bladder cancer. Our data also suggest that impairment of FAO due to downregulation of CPT1B plays an important role in the progression toward high-grade bladder cancer and provide potential targets for therapeutic intervention.",
author = "Venkatrao Vantaku and Jianrong Dong and Ambati, {Chandrashekar R.} and Dimuthu Perera and Donepudi, {Sri Ramya} and Amara, {Chandra Sekhar} and Vasanta Putluri and Ravi, {Shiva Shankar} and Robertson, {Matthew J.} and Piyarathna, {Danthasinghe Waduge Badrajee} and Mariana Villanueva and {Von Rundstedt}, {Friedrich Carl} and Balasubramanyam Karanam and Ballester, {Leomar Y.} and Terris, {Martha Kennedy} and Bollag, {Roni Jacob} and Lerner, {Seth P.} and Apolo, {Andrea B.} and Hugo Villanueva and Minjae Lee and Sikora, {Andrew G.} and Yair Lotan and Arun Sreekumar and Cristian Coarfa and Nagireddy Putluri",
year = "2019",
month = "6",
day = "15",
doi = "10.1158/1078-0432.CCR-18-1515",
language = "English (US)",
volume = "25",
pages = "3689--3701",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "12",

}

TY - JOUR

T1 - Multi-omics integration analysis robustly predicts high-grade patient survival and identifies CPT1B effect on fatty acid metabolism in Bladder Cancer

AU - Vantaku, Venkatrao

AU - Dong, Jianrong

AU - Ambati, Chandrashekar R.

AU - Perera, Dimuthu

AU - Donepudi, Sri Ramya

AU - Amara, Chandra Sekhar

AU - Putluri, Vasanta

AU - Ravi, Shiva Shankar

AU - Robertson, Matthew J.

AU - Piyarathna, Danthasinghe Waduge Badrajee

AU - Villanueva, Mariana

AU - Von Rundstedt, Friedrich Carl

AU - Karanam, Balasubramanyam

AU - Ballester, Leomar Y.

AU - Terris, Martha Kennedy

AU - Bollag, Roni Jacob

AU - Lerner, Seth P.

AU - Apolo, Andrea B.

AU - Villanueva, Hugo

AU - Lee, Minjae

AU - Sikora, Andrew G.

AU - Lotan, Yair

AU - Sreekumar, Arun

AU - Coarfa, Cristian

AU - Putluri, Nagireddy

PY - 2019/6/15

Y1 - 2019/6/15

N2 - Purpose: The perturbation of metabolic pathways in high-grade bladder cancer has not been investigated. We aimed to identify a metabolic signature in high-grade bladder cancer by integrating unbiased metabolomics, lipidomics, and transcriptomics to predict patient survival and to discover novel therapeutic targets. Experimental Design: We performed high-resolution liquid chromatography mass spectrometry (LC-MS) and bioinformatic analysis to determine the global metabolome and lipidome in high-grade bladder cancer.Wefurther investigated the effects of impaired metabolic pathways using in vitro and in vivo models. Results: We identified 519 differential metabolites and 19 lipids that were differentially expressed between low-grade and high-grade bladder cancer using the NIST MS metabolomics compendium and lipidblast MS/MS libraries, respectively. Pathway analysis revealed a unique set of biochemical pathways that are highly deregulated in high-grade bladder cancer. Integromics analysis identified a molecular gene signature associated with poor patient survival in bladder cancer. Low expression of CPT1B in high-grade tumors was associated with low FAO and low acyl carnitine levels in high-grade bladder cancer, which were confirmed using tissue microarrays. Ectopic expression of the CPT1B in high-grade bladder cancer cells led to reduced EMT in in vitro, and reduced cell proliferation, EMT, and metastasis in vivo. Conclusions: Our study demonstrates a novel approach for the integration of metabolomics, lipidomics, and transcriptomics data, and identifies a common gene signature associated with poor survival in patients with bladder cancer. Our data also suggest that impairment of FAO due to downregulation of CPT1B plays an important role in the progression toward high-grade bladder cancer and provide potential targets for therapeutic intervention.

AB - Purpose: The perturbation of metabolic pathways in high-grade bladder cancer has not been investigated. We aimed to identify a metabolic signature in high-grade bladder cancer by integrating unbiased metabolomics, lipidomics, and transcriptomics to predict patient survival and to discover novel therapeutic targets. Experimental Design: We performed high-resolution liquid chromatography mass spectrometry (LC-MS) and bioinformatic analysis to determine the global metabolome and lipidome in high-grade bladder cancer.Wefurther investigated the effects of impaired metabolic pathways using in vitro and in vivo models. Results: We identified 519 differential metabolites and 19 lipids that were differentially expressed between low-grade and high-grade bladder cancer using the NIST MS metabolomics compendium and lipidblast MS/MS libraries, respectively. Pathway analysis revealed a unique set of biochemical pathways that are highly deregulated in high-grade bladder cancer. Integromics analysis identified a molecular gene signature associated with poor patient survival in bladder cancer. Low expression of CPT1B in high-grade tumors was associated with low FAO and low acyl carnitine levels in high-grade bladder cancer, which were confirmed using tissue microarrays. Ectopic expression of the CPT1B in high-grade bladder cancer cells led to reduced EMT in in vitro, and reduced cell proliferation, EMT, and metastasis in vivo. Conclusions: Our study demonstrates a novel approach for the integration of metabolomics, lipidomics, and transcriptomics data, and identifies a common gene signature associated with poor survival in patients with bladder cancer. Our data also suggest that impairment of FAO due to downregulation of CPT1B plays an important role in the progression toward high-grade bladder cancer and provide potential targets for therapeutic intervention.

UR - http://www.scopus.com/inward/record.url?scp=85067434462&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067434462&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-18-1515

DO - 10.1158/1078-0432.CCR-18-1515

M3 - Article

VL - 25

SP - 3689

EP - 3701

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 12

ER -