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Single cell atlas identifies lipid-processing and immunomodulatory endothelial cells in healthy and malignant breast

ABSTRACT: Single cell atlas identifies lipid-processing and immunomodulatory endothelial cells in healthy and malignant breast

PROVIDER: PRJNA648429 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12319600_1.fastq.gz	Fastqsanger.gz
	SRR12319600_2.fastq.gz	Fastqsanger.gz
	SRR12319700_1.fastq.gz	Fastqsanger.gz
	SRR12319700_2.fastq.gz	Fastqsanger.gz
	SRR12319800_1.fastq.gz	Fastqsanger.gz

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Single cell atlas identifies lipid-processing and immunomodulatory endothelial cells in healthy and malignant breast

Project description:Since a detailed inventory of endothelial cell (EC) heterogeneity in breast cancer (BC) is lacking, we perform single cell RNA-sequencing of 26,515 cells (including 8,433 ECs) from 9 BC patients and compare them to published EC taxonomies from lung tumors. Angiogenic ECs are phenotypically similar, while other EC subtypes are different. Predictive interactome analysis reveals known but also previously unreported receptor-ligand interactions between ECs and immune cells, suggesting an involvement of breast EC subtypes in immune responses. We also identify a capillary EC subtype (LIPEC (Lipid Processing EC)), which expresses genes involved in lipid processing that are regulated by PPAR-gamma and is more abundant in peri-tumoral breast tissue. Retrospective analysis of 4,648 BC patients reveals that treatment with metformin (an indirect PPAR-gamma agonist) provides long-lasting clinical benefit and is positively associated with LIPEC abundance. Our findings warrant further exploration of this LIPEC/PPAR-gamma link for BC treatment.

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Project description:Maternal obesity and gestational diabetes mellitus (GDM) are associated with adverse intrauterine environments that are high in circulating nutrients. These adverse environments facilitate impairments in placental mitochondrial function and nutrient processing that ultimately leads to an increased risk of the exposed offspring developing non-communicable cardiometabolic health disorders (e.g. obesity, type 2 diabetes, metabolic syndrome). Analysis of fasting serum lipid levels in the third trimester has highlighted that Palmitate (PA) and oleate (OA) are the most abundance non-esterified fatty acids (NEFAs) in circulation. More importantly, these important NEFAs are elevated in both obese and GDM pregnancies. As PA and OA are the most abundant NEFAs in the typical “Westernized Diet” they elevated levels in obese and GDM pregnancies may highlight increased maternal consumption of these fats and could be a link between poor diet and abberant placental function. However, the independent and combined impacts of dietary PA and OA on mitochondrial function and nutrient processing in placental trophoblast cells remains poorly defined. Thus, in this study we sought to utilize a multi-omics approach (combining transcriptomics with untargeted metabolomics and lipidomics) to elucidate the underlying impacts of elevated NEFA levels on BeWo placental trophoblast cells. We highlighted a significant enrichment in the Wikipathways Fatty Acid Biosynthesis Pathway in BeWo cytotrophoblast cells treated with a combination of PA and OA (P/O; 50 µM each). Further, we identified differential expression of genes involved in lipid processing (e.g. ACADVL, ACACB, ACSL5, CREB3L3, PLIN2, and SCD) in BeWo cytotrophoblast cells treated with dietary NEFA species. Overall, these data highlighted that alterations in lipid processing, storage, and oxidation are implicated in the development of placental dysfunction in response to elevated lipid levels.

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