Single-Cell RNA-seq Reveals Obesity-Induced Alterations in the BRAC1 Mutant Mammary Tumor Microenvironment
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ABSTRACT:
PROVIDER: PRJNA640665 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12057549.fastq.gz | Fastqsanger.gz | |||
| SRR12057550.fastq.gz | Fastqsanger.gz | |||
| SRR12057551.fastq.gz | Fastqsanger.gz | |||
| SRR12057552.fastq.gz | Fastqsanger.gz |
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Project description:In this study, we conducted single-cell RNA sequencing (scRNA-seq) studies to investigate the impact of high-fat diet (HFD)-induced obesity on transcriptomic landscapes of stromal and immune cells in mammary glands of Brca1-/-;p53+/- mice, an animal breast cancer model. The scRNA-seq profiling data showed that five different subtypes of stromal fibroblasts existed in mouse mammary glands. HFD-induced obesity led to upregulated expression of extracellular matrix (ECM) genes (Col3a1, Col6a3, Eln, and Sparc) and downregulated expression of immunoregulatory genes (Iigp1, Ccl2, and Cxcl10) in these stromal subtype cells. These findings, taken together, suggest that obesity alters the ECM composition and immune ecosystem through modulating the functionality of mammary stromal cells. Moreover, scRNA-seq analysis of mammary immune cells indicated that HFD-induced obesity promoted the generation and/or recruiting of pro-tumorigenic M2 macrophages in mammary glands.
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Project description:Younger age and obesity increase the incidence and rates of metastasis of triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer. The tissue microenvironment, specifically the extracellular matrix (ECM), is known to promote tumor invasion and metastasis. We sought to characterize the effect of both age and obesity on the ECM of mammary fat pads. We used a diet-induced obesity (DIO) model where 10-week-old female mice were fed a high-fat diet (HFD) for 16 weeks or a control chow diet (CD) where time points were every 4 weeks to monitor age and obesity HFD progression. We isolated the mammary fat pads to characterize the ECM at each time point. Utilizing proteomics, we found that the early stages of obesity were sufficient to induce distinct differences in the ECM composition of mammary fat pads that promote TNBC cell invasion. ECM proteins previously implicated in driving TNBC invasion Collagen IV and Collagen VI, were enriched with weight gain. Together these data implicate ECM changes in the primary tumor microenvironment as mechanisms by which age and obesity contribute to breast cancer progression.
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Project description:We explored early changes in gene expression in the livers and lungs of the HFD-fed, metastasizing mammary tumor-bearing and obesity-resistant mice mice. These alterations may have led to favorable conditions for both the formation of pro-inflammatory and pro-mitotic microenvironments in the target organs that promote immune cell infiltration and differentiation, as well as infiltration and proliferation of metastatic tumor cells.
2012-03-05 | GSE36211 | GEO
Project description:We explored early changes in gene expression in the livers and lungs of the HFD-fed, metastasizing mammary tumor-bearing and obesity-resistant mice mice. These alterations may have led to favorable conditions for both the formation of pro-inflammatory and pro-mitotic microenvironments in the target organs that promote immune cell infiltration and differentiation, as well as infiltration and proliferation of metastatic tumor cells. Total RNA was isolated from hepatic and pulmonary tissues of high fat diet fed-4T1 cell-injected mice or high fat diet fed-sham mice. Gene expressions were compared to control diet fed-same conditional mice.
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Project description:Epidemiological studies highlight a strong association between obesity and colorectal cancer (CRC). This association appears stronger in men and a role for sex hormones is indicated by epidemiological studies. Especially estrogen is protective against CRC and correlated to several aspects of the metabolic syndrome. Anti-inflammatory and anti-tumorigenic effects of estrogen in colon have been demonstrated to act via estrogen receptor beta (ERβ). This led us to hypothesize that estrogenic signaling, through both systemic and local effects might modulate the colon microenvironment during HFD-induced obesity. In order to test our hypothesis mice were fed a control diet or a high fat diet (HFD) for 3 weeks and treated with different estrogenic ligands. In the present study, we demonstrate that there are sex-differences in the response to HFD-induced obesity and in the colon transcriptome. Both sexes develop obesity with an impaired circadian rhythm but the male metabolic profile is more sensitive to HFD and increased the colon epithelial cell proliferation. Females were resistant to impaired glucose metabolism, but HFD-feeding increased the infiltration of macrophages. Estrogen signaling in males, via ERα, presented anti-obesogenic effects. However, systemic and/or local activation of both ERα and ERβ restored the circadian rhythm in the males. In females, systemic activation of ERα restored the circadian rhythm, however, systemic and/or local activation of ERβ down-regulated the expression of macrophage markers. These results suggest that estrogen signaling through systemic and/or local activation of ERβ can regulate the colon microenvironment during HFD-induced obesity.
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