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Investigating the effects on the tumour and tumour environment transcriptome, of inhibiting PKC in conjunction with Docetaxel treatment [RNA-seq]

ABSTRACT: The breast tumour microenvironment (TME) includes fibroblasts, adipocytes, inflammatory and immune cells. While treatment of tumours with chemotherapeutic agents such as Docetaxel, leads to apoptosis of tumour cells, it can also have consequences for the cellular makeup and transcriptional profile of the TME and these, like increased epithelial mesenchymal transition can promote undesirable consequences, such as Cancer Stem Cell development. PKC-theta may have a role in these undesired effects. To be able to examine the effects of co-treatment of Docetaxel with an inhibitor of PKC-theta, we performed RNA-seq on tumours from mice injected with the human breast cancer cell line MDA-MB-231. We then separated reads mapped to the human and mouse genomes in silico, creating tumour and TME transcriptomes for control, Docetaxel, PKC-theta inhibitor and combination treated mice. Separation of the tumour and TME profiles illustrated a role for PKC-theta in the induction of a more basal-type transcriptome in the tumour, and of EMT in the TME.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE137467 | GEO | 2022/09/14

REPOSITORIES: GEO

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Project description:Malignant germ-cell-tumours (GCTs) are characterised by microRNA (miRNA/miR-) dysregulation, with universal over-expression of miR-371~373 and miR-302/367 clusters regardless of patient age, tumour site, or subtype (seminoma/yolk-sac-tumour/embryonal carcinoma). These miRNAs are released into the bloodstream, presumed within extracellular-vesicles (EVs) and represent promising biomarkers. Here, we comprehensively examined the role of EVs, and their miRNA cargo, on (fibroblast/endothelial/macrophage) cells representative of the testicular GCT (TGCT) tumour microenvironment (TME). Small RNA next-generation-sequencing was performed on 34 samples, comprising representative malignant GCT cell lines/EVs and controls (testis fibroblast [Hs1.Tes] cell-line/EVs and testis/ovary samples). TME cells received TGCT co-culture, TGCT-derived EVs, and a miRNA overexpression system (miR-371a-OE) to assess functional relevance. TGCT cells secreted EVs into culture media. MiR-371~373 and miR-302/367 cluster miRNAs were overexpressed in all TGCT cells/subtypes compared with control cells and were highly abundant in TGCT-derived EVs, with miR-371a-3p/miR-371a-5p the most abundant. TGCT co-culture resulted in increased levels of miRNAs from the miR-371~373 and miR-302/367 clusters in TME (fibroblast) cells. Next, fluorescent labelling demonstrated TGCT-derived EVs were internalised by all TME (fibroblast/endothelial/macrophage) cells. TME (fibroblast/endothelial) cell treatment with EVs derived from different TGCT subtypes resulted in increased miR-371~373 and miR-302/367 miRNA levels, and other generic (eg, miR-205-5p/miR-148-3p) and subtype-specific (seminoma, eg, miR-203a-3p; yolk-sac-tumour, eg, miR-375-3p) miRNAs. MiR-371a-OE in TME cells resulted in increased collagen contraction (fibroblasts) and angiogenesis (endothelial cells), via direct mRNA downregulation and alteration of relevant pathways. TGCT cells communicate with nontumour stromal TME cells through release of EVs enriched in oncogenic miRNAs, potentially contributing to tumour progression.

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Investigating the effects on the tumour and tumour environment transcriptome, of inhibiting PKC in conjunction with Docetaxel treatment [RNA-seq]

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