Lung cancer remains the leading cause of cancer death worldwide and non-small cell lung carcinoma (NSCLC) represents 85% of newly diagnosed lung cancers. In this study, we utilized our untargeted assignment tool Small Molecule Isotope Resolved Formula Enumerator (SMIRFE) and ultra-high-resolution Fourier transform mass spectrometry to examine lipid profile differences between paired cancerous and non-cancerous lung tissue samples from 86 patients with suspected stage I or IIA primary NSCLC. Correlation and co-occurrence analysis revealed significant lipid profile differences between cancer and non-cancer samples. Further analysis of machine-learned lipid categories for the differentially abundant molecular formulas identified a high abundance sterol, high abundance and high m/z sphingolipid, and low abundance glycerophospholipid metabolic phenotype across the NSCLC samples. At the class level, high abundances of sterol esters and cardiolipins were observed suggesting altered stearoyl-CoA desaturase 1 (SCD1) or acetyl-CoA acetyltransferase (ACAT1) activity and altered human cardiolipin synthase 1 or lysocardiolipin acyltransferase activity respectively, the latter of which is known to confer apoptotic resistance. The presence of a shared metabolic phenotype across a variety of genetically distinct NSCLC subtypes suggests that this phenotype is necessary for NSCLC development and may result from multiple distinct genetic lesions. Thus, targeting the shared affected pathways may be beneficial for a variety of genetically distinct NSCLC subtypes

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Published in Metabolites, v. 11, issue 11, 740.

© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

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The work was supported in part by grants NSF 1419282 (PI Moseley), NSF 2020026 (PI Moseley), NIH 1P01CA163223-01A1 (PD Lane), 1U24DK097215-01A1 (PD Higashi), and P30 CA177558 (B.M. Evers, PI) via the Markey Cancer Center Biostatistics and Bioinformatics Shared Resource Facility (MCC BB-SRF).

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All data and results presented here are available in a FigShare repository: DOI: https://www.doi.org/10.6084/m9.figshare.14199521.v3. This includes characterized peaks derived from Fourier transform mass spectra and all downstream analyses of these characterized peak lists.

The following are available online at https://www.mdpi.com/article/10.3390/metabo11110740/s1, Figure S1: PCA of Consistently Assigned Spectral Features by Instrument, Figure S2: Abundance heatmap of consistently assigned lipids in non-cancer and cancer samples, with statin use indicated, Table S1: Demographic Information NSCLC. The materials are also available for download as the additional file listed at the end of this record.

metabolites-11-00740-s001.zip (790 kB)
Supplementary file