Metabolomics revealed the influence of breast cancer on lymphatic endothelial cell metabolism, metabolic crosstalk, and lymphangiogenic signaling in co-culture

Abstract

Breast cancer metastasis occurs via blood and lymphatic vessels. Breast cancer cells ‘educate’ lymphatic endothelial cells (LECs) to support tumor vascularization and growth. However, despite known metabolic alterations in breast cancer, it remains unclear how lymphatic endothelial cell metabolism is altered in the tumor microenvironment and its effect in lymphangiogenic signaling in LECs. We analyzed metabolites inside LECs in co-culture with MCF-7, MDA-MB-231, and SK-BR-3 breast cancer cell lines using $$^1\hbox {H}$$ 1 H nuclear magnetic resonance (NMR) metabolomics, Seahorse, and the spatial distribution of metabolic co-enzymes using optical redox ratio imaging to describe breast cancer-LEC metabolic crosstalk. LECs co-cultured with breast cancer cells exhibited cell-line dependent altered metabolic profiles, including significant changes in lactate concentration in breast cancer co-culture. Cell metabolic phenotype analysis using Seahorse showed LECs in co-culture exhibited reduced mitochondrial respiration, increased reliance on glycolysis and reduced metabolic flexibility. Optical redox ratio measurements revealed reduced NAD(P)H levels in LECs potentially due to increased NAD(P)H utilization to maintain redox homeostasis. $$^{13}\hbox {C}$$ 13 C -labeled glucose experiments did not reveal lactate shuttling into LECs from breast cancer cells, yet showed other $$^{13}\hbox {C}$$ 13 C signals in LECs suggesting internalized metabolites and metabolic exchange between the two cell types. We also determined that breast cancer co-culture stimulated lymphangiogenic signaling in LECs, yet activation was not stimulated by lactate alone. Increased lymphangiogenic signaling suggests paracrine signaling between LECs and breast cancer cells which could have a pro-metastatic role.

Common and diet-specific metabolic pathways underlying residual feed intake in fattening Charolais yearling bulls

“…We aimed to compare how Low- and High-RFI metabolite profiles contrasted over the two diets. Therefore, when a significant RFI Diet interaction was detected, pairwise comparisons performed by Tukey’s honestly significance difference were only applied within each diet (sliced comparisons) as previously reported 64 , 67 . Given the relatively small change in the plasma metabolite concentration expected across individuals fed the same diet but differing in RFI, no restrictive threshold fold-change cut-off was applied when interpreting FDR significant metabolites 10 , 68 .…”

Mathematical reconstruction of the metabolic network in anin-vitromultiple myeloma model

“…The copyright holder for this preprint this version posted September 15, 2022. ; https://doi.org/10.1101/2022.09.12.507672 doi: bioRxiv preprint many previous studies on multiple cancer cell types [99,100]. For instance, it has been hypothesised that lactate is not only a by-product of a malignancy's highly glycolytic metabolism but can be salvaged by other cell types for mitochondrial oxidative energy production [28,101,102].…”

In Vitro, In Vivo, and In Silico Models of Lymphangiogenesis in Solid Malignancies

“…In the context of increasing computational capabilities going together with the big data era, bioinformatics tools are essential for the treatment and analysis of these data. Transcriptomic and single-cell data from (lymph node) lymphatic vasculature [197][198][199][200][201], as well as metabolomic [202] and proteomic [203,204] data, have already been produced from experimental lymphatic set-ups. In combination with imaging techniques, Williams et al also used bioinformatics approaches to study the impact of particular siRNAs on the 2D in vitro migration of endothelial cells [68].…”