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Title: MALDI-Mass Spectrometric Imaging Revealing Hypoxia-Driven Lipids and Proteins in a Breast Tumor Model

Hypoxic areas are a common feature of rapidly growing malignant tumors and their metastases, and are typically spatially heterogeneous. Hypoxia has a strong impact on tumor cell biology and contributes to tumor progression in multiple ways. To date, only a few molecular key players in tumor hypoxia, such as for example hypoxia-inducible factor-1 (HIF-1), have been discovered. The distribution of biomolecules is frequently heterogeneous in the tumor volume, and may be driven by hypoxia and HIF-1α. Understanding the spatially heterogeneous hypoxic response of tumors is critical. Mass spectrometric imaging (MSI) provides a unique way of imaging biomolecular distributions in tissue sections with high spectral and spatial resolution. In this paper, breast tumor xenografts grown from MDA-MB-231-HRE-tdTomato cells, with a red fluorescent tdTomato protein construct under the control of a hypoxia response element (HRE)-containing promoter driven by HIF-1α, were used to detect the spatial distribution of hypoxic regions. We elucidated the 3D spatial relationship between hypoxic regions and the localization of small molecules, metabolites, lipids, and proteins by using principal component analysis – linear discriminant analysis (PCA-LDA) on 3D rendered MSI volume data from MDA-MB-231-HRE-tdTomato breast tumor xenografts. In this study we identified hypoxia-regulated proteins active in several distinct pathways suchmore » as glucose metabolism, regulation of actin cytoskeleton, protein folding, translation/ribosome, splicesome, the PI3K-Akt signaling pathway, hemoglobin chaperone, protein processing in endoplasmic reticulum, detoxification of reactive oxygen species, aurora B signaling/apoptotic execution phase, the RAS signaling pathway, the FAS signaling pathway/caspase cascade in apoptosis and telomere stress induced senescence. In parallel we also identified co-localization of hypoxic regions and various lipid species such as PC(16:0/18:1), PC(16:0/18:2), PC(18:0/18:1), PC(18:1/18:1), PC(18:1/18:2), PC(16:1/18:4), PC(18:0/20:3), PC(16:0/22:1), among others. Lastly, our findings shed light on the biomolecular composition of hypoxic tumor regions, which may be responsible for a given tumor’s resistance to radiation or chemotherapy.« less
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [4] ;  [3] ;  [5] ;  [4]
  1. Johns Hopkins Univ., Baltimore, MD (United States). Division of Cancer Imaging Research, Russell H. Morgan Dept. of Radiology and Radiological Science
  2. Fundamental Research on Matter (FOM) AMOLF, Amsterdam (The Netherlands)
  3. Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Environmental Molecular Sciences Lab. (EMSL)
  4. Johns Hopkins Univ., Baltimore, MD (United States). Division of Cancer Imaging Research, Russell H. Morgan Dept. of Radiology and Radiological Science; Johns Hopkins Univ., Baltimore, MD (United States). School of Medicine, Sidney Kimmel Comprehensive Cancer Center
  5. Fundamental Research on Matter (FOM) AMOLF, Amsterdam (The Netherlands); Maastricht MultiModal Molecular Imaging Institute (M4I), Maastricht (The Netherlands)
Publication Date:
OSTI Identifier:
1203872
Report Number(s):
PNNL-SA-110776
Journal ID: ISSN 0003-2700; 40892; KP1704020
Grant/Contract Number:
AC05-76RL01830; R01 CA134695; R01 CA154725
Type:
Accepted Manuscript
Journal Name:
Analytical Chemistry
Additional Journal Information:
Journal Volume: 87; Journal Issue: 12; Journal ID: ISSN 0003-2700
Publisher:
American Chemical Society (ACS)
Research Org:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org:
USDOE; National Institutes of Health (NIH)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; breast cancer; mass spectrometric imaging; hypoxia, phosphatidylcholine; lipid, peptide; protein; Environmental Molecular Sciences Laboratory