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Lipid-restricted culture media reveals unexpected cancer cell sensitivities

ABSTRACT: Cancer cell culture models frequently rely on fetal bovine serum as a source of protein and lipid factors that support cell survival and proliferation; however, serum-containing media imperfectly mimics the in vivo cancer environment. Recent studies suggest that typical serum-containing cell culture conditions can mask cancer dependencies, for example on cholesterol biosynthesis enzymes, that exist in vivo and emerge when cells are cultured in media that provides more realistic levels of lipids. Here we describe a high-throughput screen that identified fenretinide and ivermectin as small molecules whose cytotoxicity is greatly enhanced in lipid-restricted media formulations. Mechanism of action studies indicate that the ivermectin-induced cell death involves oxidative stress, while fenretinide likely targets DEGS1, a lipid desaturase necessary for ceramide synthesis, to induce cell death. Notably, both fenretinide and ivermectin have previously demonstrated in vivo anticancer efficacy despite their low cytotoxicity under typical cell culture conditions. These studies reveal ceramide synthesis as a targetable vulnerability of cancer cells cultured under lipid-restricted conditions and suggest a general screening strategy for identifying additional cancer dependencies masked by culture conditions unrepresentative of the in vivo environment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247900 | GEO | 2024/11/14

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE247900_FenvDel_Differentially_expressed.txt.gz	Txt
	GSE247900_IvvDel_Differentially_expressed.txt.gz	Txt
	GSE247900_LipvDel_Differentially_expressed.txt.gz	Txt
	GSE247900_TPM.txt.gz	Txt

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Project description:Background: Since the development of in vitro embryo production in cattle, different supplements have been added to embryo culture media to support development, with serum being the most popular. However, the addition of serum during embryo culture can induce high birth weights and low viability in calves (Large Offspring Syndrome). Global gene expression analysis of bovine embryos through RNA sequencing produced in different conditions (in vivo, in vitro with serum added and in vitro without addition of serum) can provide valuable information to optimize culture media for in vitro embryo production, which is necessary to obtain healthy offspring. Results: Here, we used RNA sequencing to examine the effect of in vitro embryo production, either in serum or in serum-free conditions, on the global gene expression pattern of individual bovine blastocysts. For this purpose, we compared in vitro produced with in vivo derived embryos. The embryos produced in serum had ten times more genes differentially expressed than the embryos produced in serum-free conditions (1,106 vs. 110). Importantly, in vitro production appeared to have a different impact on the embryos according to their sex, with male embryos showing more deviations in their gene expression pattern than their female counterparts. In particular, embryos produced in the presence of serum showed the largest difference, with male embryos having eight times more genes differentially expressed than the females (1,561 vs. 200). This difference was reduced when the embryos were produced in serum-free conditions, where the male embryos had only about double the number of genes differentially expressed than their female counterparts (64 vs. 35). The pathways affected by in vitro production differed depending on the supplementation. While embryos produced in serum conditions had altered genes involved in RNA processing and mitosis, embryos produced in serum-free conditions showed aberrations in genes involved in lipid metabolism. Conclusions: Serum supplementation had a major impact on the gene expression pattern of the embryos. On the contrary, the transcriptome of embryos produced in serum-free conditions resembled more in vivo derived embryos, although genes involved in lipid metabolism were altered. Male embryos appeared to be most affected by in vitro production, especially after serum supplementation.

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Lipid-restricted culture media reveals unexpected cancer cell sensitivities

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