; We propose a systems biochemical study of lung cancer (LC) cell nutrient metabolism of importance to LC development, survival and progression in the tumor microenvironment (TME). The primary approach is to utilize stable isotopic (13C and 15N) nutrient tracers in conjunction with stable isotope-resolved metabolomics (SIRM) and metabolomics-edited transcriptomic analysis (META) to discern key metabolic events in LC cells that govern their behavior and vulnerability in response to major TME factors such as hypoxia and nutrient deficiency. A central focus of this cell-based project is to understand the interaction of nutrient availability and hypoxia in modulating LC cell metabolism and how this may affect its ability to grow, survive and progress. This focus is in part motivated by our recent finding from the gene array data of paired cancerous and benign lung tissues resected from human patients regarding the dysregulations of key enzymes (e.g. arginase, glutaminase, hyaluronan synthase 2) involved in metabolism of glutamine and glucose. It is also driven by our recent discovery of arginase suppression in lung tumor xenograft and activation of Gin metabolism in murine macrophages by a natural immune activator, B-glucan. We will accomplish this with the following specific aims: SAI: SIRM profiling of lung cells for reconstructing biochemical pathways involved in utilization of glucose and glutamine. Biochemical pathways of these nutrients relevant to energy, anabolism, immunomodulatory sensors, and cell migration-related extracellular matrix factors will be mapped in LC cells harboring major driver gene anomalies, normal epithelial cells, and relevant stromal cells for comparison. SA2: Probe interactions of nutrient availability in combination with hypoxia. We will focus on 2 key questions: 1) How does Gin alleviate glucose demand by LC cells?;2) Is Gin metabolism crucial to hypoxic LC cells?. SAS: Examine Arg metabolism in human tumor-associated macrophages as a function of Gin and Arg availability. Gin and Arg utilization pathways of relevance to immunomodulation in tumor-associated human macrophages will be probed in response to immune activator (B-glucans) and M2 to Ml polarization. The knowledge gained from this project will be used to help interpret data obtained from Projects 2 and 3.

Public Health Relevance

Deaths from lung cancer are the highest among all cancers in North America and cure rates remain low. We seek to gain a deeper understanding of lung cancer biochemistry using a novel approach we developed. Improved knowledge will have direct impact on early diagnosis and prognosis. The biochemical differences between lung cancer subtypes can be related to appropriate treatments.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
7P01CA163223-02
Application #
8744921
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
2014-08-19
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
2
Fiscal Year
2014
Total Cost
$273,326
Indirect Cost
$69,232
Name
University of Kentucky
Department
Type
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Yang, Ye; Fan, Teresa W-M; Lane, Andrew N et al. (2017) Chloroformate derivatization for tracing the fate of Amino acids in cells and tissues by multiple stable isotope resolved metabolomics (mSIRM). Anal Chim Acta 976:63-73
Lane, Andrew N; Fan, Teresa W-M (2017) NMR-based Stable Isotope Resolved Metabolomics in systems biochemistry. Arch Biochem Biophys 628:123-131
Yan, J (2017) Identifying biomarkers in human psoriasis: revealed by a systems metabolomics approach. Br J Dermatol 176:555-557
Zhao, Jiangsha; Li, Jieran; Fan, Teresa W M et al. (2017) Glycolytic reprogramming through PCK2 regulates tumor initiation of prostate cancer cells. Oncotarget 8:83602-83618
Sun, Ramon C; Fan, Teresa W-M; Deng, Pan et al. (2017) Noninvasive liquid diet delivery of stable isotopes into mouse models for deep metabolic network tracing. Nat Commun 8:1646
Bruntz, Ronald C; Lane, Andrew N; Higashi, Richard M et al. (2017) Exploring cancer metabolism using stable isotope-resolved metabolomics (SIRM). J Biol Chem 292:11601-11609
Fan, Teresa W-M; Warmoes, Marc O; Sun, Qiushi et al. (2016) Distinctly perturbed metabolic networks underlie differential tumor tissue damages induced by immune modulator ?-glucan in a two-case ex vivo non-small-cell lung cancer study. Cold Spring Harb Mol Case Stud 2:a000893
Lane, Andrew N; Higashi, Richard M; Fan, Teresa W-M (2016) Preclinical models for interrogating drug action in human cancers using Stable Isotope Resolved Metabolomics (SIRM). Metabolomics 12:
Li, Jing; Song, Jun; Zaytseva, Yekaterina Y et al. (2016) An obligatory role for neurotensin in high-fat-diet-induced obesity. Nature 533:411-5
Albeituni, Sabrin H; Ding, Chuanlin; Liu, Min et al. (2016) Yeast-Derived Particulate ?-Glucan Treatment Subverts the Suppression of Myeloid-Derived Suppressor Cells (MDSC) by Inducing Polymorphonuclear MDSC Apoptosis and Monocytic MDSC Differentiation to APC in Cancer. J Immunol 196:2167-80

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