The gold standard for understanding the connection between tumor metabolism, tumor progression and ultimately therapeutic efficacy is the human subject, but more detailed information is needed from appropriate better controlled models. We have begun a Stable Isotope Resolved Metabolomics (SIRM) study of non-small cell lung cancer (NSCLC) from patients who underwent surgical resection. In our pilot study we capitalized on the inherent power of the matched pairs of malignant and benign lung tissue and the use of """"""""C-labeled glucose administered iv prior to surgery to map in situ intracellular metabolic pathways for the first time. This led to the discovery that mitochondrial pyruvate carboxylase (PCB) is activated to replenish Krebs cycle intermediates required for biosynthesis (i.e. anaplerosis) in tumors. This was further corroborated by increased mRNA and protein expression of PCB in the tumors compared with the paired benign lung tissue, as well as growth inhibition of NSCLC cells by PCB knockdown. Critical to the interpretation of these studies was the additional detailed information that we obtained on cell culture, and mouse models, which provided metabolic signatures to look for in the tumor tissue.). Our preliminary findings also indicate that there are many more metabolic distinctions in lung tumors;the underlying pathways and regulation have yet to be defined. We now seek to extend the approach to a larger cohort of NSCLC and added a new ex vivo """"""""Warburg"""""""" tissue slice approach to better define in large-scale the metabolic reprogrammings in NSCLC with prevailing driver gene defects. These direct human studies will be conducted in parallel with model cell (Project 1) and animal studies (Project 2) to facilitate interpretation. We will also apply this integrated approach to explore the metabolic mechanism underlying the tumor-regressive effect of a pre-operative treatment with beta-glucans. We hypothesize that this effect may be in part mediated by beta-glucan's activation of glucose and Gin metabolism in resident macrophages, a key immune modulator in the tumor microenvironment, based on our most recent data and the literature (cf. Project 2). We will further explore the linkage of lung tumor tissue to blood plasma metabolism via the lipidic microvesicles (MV), known to be released by lung cancer cells with metastasis-promoting capacity. We have new evidence that the lipid profile of plasma MV is distinct among early stages of lung and breast cancer patients and healthy subjects. We will test if beta-glucan treatment can alter MV metabolic signatures for future application as clinical indicators. These goals will be achieved via the three specific aims.

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 #
1P01CA163223-01A1
Application #
8458686
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (O1))
Project Start
2013-03-01
Project End
2018-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
1
Fiscal Year
2013
Total Cost
$296,727
Indirect Cost
$98,909
Name
University of Louisville
Department
Type
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
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 β-glucan in a two-case ex vivo non-small-cell lung cancer study. Cold Spring Harb Mol Case Stud 2:a000893
Albeituni, Sabrin H; Ding, Chuanlin; Liu, Min et al. (2016) Yeast-Derived Particulate β-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
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
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:
Krem, Maxwell M; Yan, Jun (2016) To b(ortezomib) or not to be: the stroma's the thing. J Pathol 240:123-5
Fan, Teresa W-M; Lane, Andrew N (2016) Applications of NMR spectroscopy to systems biochemistry. Prog Nucl Magn Reson Spectrosc 92-93:18-53
Fan, Teresa W-M; Lane, Andrew N; Higashi, Richard M (2016) Stable Isotope Resolved Metabolomics Studies in Ex Vivo TIssue Slices. Bio Protoc 6:
Lane, Andrew N; Arumugam, Sengodagounder; Lorkiewicz, Pawel K et al. (2015) Chemoselective detection and discrimination of carbonyl-containing compounds in metabolite mixtures by 1H-detected 15N nuclear magnetic resonance. Magn Reson Chem 53:337-43
Liu, Min; Luo, Fengling; Ding, Chuanlin et al. (2015) Dectin-1 Activation by a Natural Product β-Glucan Converts Immunosuppressive Macrophages into an M1-like Phenotype. J Immunol 195:5055-65
Tarrado-Castellarnau, Míriam; Cortés, Roldán; Zanuy, Miriam et al. (2015) Methylseleninic acid promotes antitumour effects via nuclear FOXO3a translocation through Akt inhibition. Pharmacol Res 102:218-34

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