Type 2 immunity is maintained during cancer associated adipose tissue wasting

ABSTRACT: Purpose: Cachexia is a metabolic phenotype affecting many cancer patients. The immune environment in adipose tissue during the development of cancer associated cachexia has not been characterized. To help address this gap, we isolated visceral adipose tissue from cancer-bearing and sham-operated mice and performed bulk RNA-sequencing. Methods: mRNA expression was evaluated by RNA-sequencing in visceral adipose tissue (VAT) of 10-week old mice which had been subjected to sham surgery (sham) or had received orthotopic pancreatic tumors four weeks prior to harvest (KPC). Paired-end 150 bp single-index sequencing was performed using an Illumina HiSeq system. Transcript quantification was performed with Salmon, using quasi-mapping mode with selective alignment (validateMappings). We set the rangeFactorizationBins to 4 and passed both the seqBias and gcBias flags to correct for sequence-specific bias and fragment-level GC bias, respectively. Transcript quantifications were collapsed to gene-level quantifications using the tximport package and the Ensembl based annotation package EnsDb.Mmusculus.v79. Differential expression analysis was then performed using DESeq2 with fold change shrinkage by ashr. For downstream analysis and visualization, only genes with a mean TPM (transcripts per million) > 2 in VAT from both sham-operated and tumor-bearing mice were considered. Results: We identified over 11,000 genes which were expressed at an average of at least 2 TPM (transcripts per million) in both the sham and KPC adipose tissue samples. Differential expression analysis with DESeq revealed 161 upregulated genes (p < 0.05) and 27 downregulated genes (p < 0.05) in the adipose tissue of cancer bearing mice compared to that of sham operated mice. Gene set enrichment analysis suggested an increase in inflammatory pathways, including type 1 and type 2 interferon pathways, in the adipose tissue of cancer bearing mice. Conclusions: This study represents a comprehensive characterization of adipose tissue in the healthy vs. cachexia setting. The RNA-seq data suggests increased immune infiltration into adipose tissue in the setting of a distant pancreatic tumor. Together with flow cytometry and cytokine abundance analyses, we conclude that reguatory Th2 immunity is maintained in the adipose tissue during this model of cancer associated cachexia.

ORGANISM(S): Mus musculus

PROVIDER: GSE171402 | GEO | 2021/04/03

REPOSITORIES: GEO