Untargeted Lipidomics of NSCLC Shows Differentially Abundant Lipid Classes in Cancer vs Non-Cancer Tissue

Lung cancer is the leading cause of cancer death worldwide and non-small cell lung cancer (NSCLC) represents

85% of newly diagnosed lung cancers. The high mortality rate of lung cancer is due in part to the lack of effective treatment options for advanced disease. A major limitation in the development of effective treatment options is our incomplete understanding of NSCLC metabolism at a molecular level. Improvements in mass spectrometry combined with our untargeted assignment tool SMIRFE enables systematic and less biased examinations of NSCLC metabolism.

The molecular formula assignments provided by SMIRFE were then classified to lipid category and class using

machine learning models trained on known examples of lipid molecular formulas. Subsequent differential abundance

analysis of these classified formulas revealed significant and consistent differences in lipid profiles at the lipid category

level between disease and non-disease samples. Both sterols and glycerolipids were consistently and significantly

upchanged in disease versus non-disease. This pattern was also observed in the set of samples confirmed by pathology to be primary NSCLC.

The significant upchange in sterols in primary NSCLC suggests a possible therapeutic role for statins and

nitrogenous bisphosphonates, pharmaceuticals that inhibit endogenous sterol biosynthesis, in the treatment of primary

NSCLC. This hypothesis is consistent with previous epidemiological studies that have identified a therapeutic role for statins in the treatment of NSCLC, but were unable to identify a molecular mechanism for this effect. Additionally, several sterols belonging to the sterol ester subcategory are consistently and significantly upchanged, suggesting increased SCD1 activity. SCD1 expression is known to be a negative prognostic indicator for survival in NSCLC. In our study, a large fraction of the NSCLC samples displayed this phenotype; however, SCD1 mutants are unexpected in all of these samples. This suggests that this metabolic phenotype may be shared across multiple genetic subtypes of NSCLC. Thus, inhibitors of SCD1 and other enzymes involved in the production of this metabolic phenotype could have utility in the treatment of many genetic subtypes of NSCLC.