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Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer [Mammary fat pad, MFP]

ABSTRACT: Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer [Mammary fat pad, MFP]

PROVIDER: PRJNA728059 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14465526_1.fastq.gz	Fastqsanger.gz
	SRR14465526_2.fastq.gz	Fastqsanger.gz
	SRR14465527_1.fastq.gz	Fastqsanger.gz
	SRR14465527_2.fastq.gz	Fastqsanger.gz
	SRR14465528_1.fastq.gz	Fastqsanger.gz

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Project description:Direct transcriptomics comparison corroborated by functional and gene network analyses of pre-weaned bovine mammary parenchyma and fat pad shed light on potential cross-talk between these developing tissues. Transcriptomic characterization of mammary parenchyma and fat pad and their interaction is still incomplete. In the present experiment, the molecular epithelial-fat pad cross-talk during mammary development was assessed by transcript profiling and functional analyses. Background: Interactions between bovine mammary parenchyma (PAR) and fat pad (MFP) during neonatal tissue development are still not fully understood. It is thought that the MFP surrounding the parenchymal tissue exerts proliferative effects on the PAR through secretion of local modulators of growth induced by systemic hormones. Main objectives in the present study were to use bioinformatics tools to characterize differences in transcript profiles between mammary PAR and MFP from Holstein heifers at ca. 65 d age and uncover potential cross-talk between the two tissues via the analyses of signaling molecules (e.g., cytokines and growth factors) preferentially expressed in one tissue relative to the other. Results: Over 9,000 differentially expressed genes (DEG; False discovery rate ≤ 0.05) were found of which 1,478 had a ≥1.5-fold difference. Within these DEG in PAR vs. MFP (n = 736) we noted enrichment of functions related to cell cycle, structural organization, signaling, and DNA/RNA metabolism. Few canonical pathways were among DEG and were mostly involved in cell cycle and tissue organization (p53 signaling). Enriched among DEG more highly-expressed in MFP vs. PAR (n = 742) were genes involved in lipid metabolism, signaling, cell movement, and immune-related functions. Canonical pathways associated with metabolism (fatty acid metabolism) and signaling, particularly immune- (acute phase response) and metabolism-related (cAMP signaling), were significantly enriched. Network analysis uncovered a central role of MYC, TP53, and CTNNB1 in controlling expression of DEG highly-expressed in PAR vs. MFP. Similar analysis revealed a central role of PPARG, KLF2, EGR2, and EPAS1 in regulating expression of highly-expressed DEG in MFP vs. PAR. Analyses revealed putative crosstalk between tissues via differential expression of cytokines and growth factors highly-expressed in PAR (angiopoietin-1, osteopontin, interleukin-1β) or in MFP (adiponectin, interleukin-13, fibroblast growth factor-2, leptin) during bovine mammary development. Conclusions: We uncovered specific transcriptomic signatures characterizing MFP and PAR tissue. Not surprisingly, the expression profile of the MFP is characteristic of adipose tissue, and the one of PAR is characteristic of an epithelial tissue undergoing expansion and remodeling. Overall, our data highlighted a large degree of interaction between the two tissues and allowed envisaging a reciprocal influence in determining the biological features (and perhaps the fate) of each of the two tissues during this stage of development. This is strongly suggested by the potential effect that the signaling molecules released preferentially by PAR have on lipid metabolism-related pathways, which from our data was what most distinguished the MFP from PAR. Similarly, the cytokines and growth factors largely expressed in MFP potentially affect the pathways related to cell cycle, development, and proliferation in PAR, which our data highlighted as the main functions represented among the genes highly expressed in PAR vs. MFP. Based on the current analysis, the number of cytokines and growth factors that potentially are secreted by each tissue and affect molecules in the other underscores the concept of crosstalk. Ultimately, these bidirectional interactions might be required to coordinate mammary tissue development under normal circumstances or in response to environmental stimuli, such as nutrition.

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Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer [Mammary fat pad, MFP]

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