Abstract
Triple negative breast cancer (TNBC) is a particularly aggressive cancer subtype that is difficult to diagnose due to its discriminating epidemiology and obscure metabolome. For the first time, 3D spatial and chemometric analyses uncover the unique lipid metabolome of TNBC under the tandem modulation of two key metabolites – insulin and methionine - using non-invasive optical techniques. By conjugating heavy water (D2O) probed Raman scattering with label-free two-photon fluorescence (TPF) microscopy, we observed altered de novo lipogenesis, 3D lipid droplet morphology, and lipid peroxidation under various methionine and insulin concentrations. Quantitative interrogation of both spatial and chemometric lipid metabolism under tandem metabolite modulation confirms significant interaction of insulin and methionine, which may prove to be critical therapeutic targets, and proposes a powerful optical imaging platform with subcellular resolution for metabolic and cancer research.
Highlights
Breast cancer is the most reported form of cancer in biological women, but the pathophysiology is rife with subtypes that have material consequences on patient outcomes
We first examined the effects of methionine on lipid droplets (LD) metabolism in Triple negative breast cancer (TNBC) cells (MDA-MB-231), luminal A breast cancer cells (MCF-7), and normal breast epithelial cells (MCF10A, as a control) by adding excess (20x) methionine to the growth media supplemented with 50% D2O
The unique lipid metabolism of triple negative breast cancer was studied under tandem excess methionine and insulin conditions, and revealed key insights that span the metabolic, spatial, and biochemical dimensions
Summary
Breast cancer is the most reported form of cancer in biological women, but the pathophysiology is rife with subtypes that have material consequences on patient outcomes. Triple negative breast cancer (TNBC) is a aggressive cancer subtype that accounts for approximately 15% of all breast cancer cases and its epidemiology reveals a discriminating predilection for non-Hispanic African women [1, 2] (Figure S1). The genomes and proteomes of these breast cancer subtypes are distinguishable, little is known about their metabolic phenotypes and the consequential prognoses they manifest. Lipid metabolism has emerged as a major indicator of cellular stress, phenotypic state, and disease status in biological research and medicine. Dysregulation of lipid metabolism and heightened lipid synthesis are hallmarks of cancer, as varying demands of lipids for energy maintenance, metastasis, and angiogenesis warrant transcriptional changes that contribute to the metabolic phenotype [3–5].
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