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Single cell atlas of epithelial and stromal cell heterogeneity by lobe and strain in the mouse prostate

ABSTRACT: Evaluating the complex interplay of cell types in the tissue microenvironment is critical to understanding the origin and progression of diseases in the prostate and potential opportunities for intervention. Mouse models are an essential tool to investigate the molecular and cell-type-specific contributions of prostate disease at an organismal level. While there are well-documented differences in the extent, timing, and nature of disease development in various genetically engineered and exposure-based mouse models in different mouse strains and prostate lobes within each mouse strain, the underlying molecular phenotypic differences in cell types across mouse strains and prostate lobes are incompletely understood.

ORGANISM(S): Mus musculus

PROVIDER: GSE165741 | GEO | 2022/11/14

REPOSITORIES: GEO

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Project description:Cancer of the prostate is influenced both by genetic predisposition and environmental factors. The identification of genes capable of modulating cancer development has the potential to unravel disease heterogeneity and aid diagnostic and prevention strategies through improved understanding of gene-environment interactions. To this end, mouse models have been developed to isolate the influences of individual genetic lesions in the context of consistent genotypes and environmental exposures. However, the extent of normal prostatic phenotypic variability dictated by a genetic background potentially capable of influencing the process of carcinogenesis has not been established. In this study we used microarray analysis to quantitate transcript abundance levels in the prostates of five commonly studied inbred mouse strains. We applied a multiclass response t-test to identify genes whose expression in each strain significantly differed from the other four strains. Approximately 13% (932 genes) exhibited significant differential expression (range 1.3 to 190-fold) in one strain relative to other strains (FDRM-bM-^IM-$10%). The pattern of variability in transcript levels did not result from variations unique to a particular strain, but rather represented genetic variability across all five strains assessed. Expression differences were confirmed by qRT-PCR, or immunohistochemistry for several genes previously shown to influence cancer progression such as Psca, Mmp7, and Clusterin. Analyses of human prostate transcripts orthologous to variable murine prostate genes identified differences in gene expression in benign epithelium that correlated with the differentiation state of adjacent tumors. For example, the expression of apolipoprotein D, a gene known to enhance resistance to cell stress in Drosophila, was expressed at significantly greater levels in benign epithelium associated with high-grade versus low-grade cancers. These data support the concept that the cellular, tissue, and organismal context contribute to oncogenesis and suggest that a predisposition to a sequence of events leading to pathology may be determined prior to cancer initiation. Prostates from twelve mice from each of five strains of Mus musculus: C57BL/6J, 129X1/SvJ, BALB/cAnCrl, FVB/NJ and DBA/2NCrl, were resected and individual lobes were dissected: DP: dorsal prostate; LP: lateral prostate; VP: ventral prostate; AP: anterior prostate. Each experimental sample represents a pool of equal amounts of RNA for each prostatic lobe from 3 animals. Four independent experimental samples were created per strain: 12 mice divided into 4 pools of 3 mice each for a total of 4 microarray experiments per strain. Amplified RNA from each experimental sample was hybridized against a reference sample (created by combining equal amounts of RNA from all the samples from all strains) onto custom mouse prostate cDNA microarrays using alternate dye-labeling to account for dye-specific effects.

Project description:Cancer of the prostate is influenced both by genetic predisposition and environmental factors. The identification of genes capable of modulating cancer development has the potential to unravel disease heterogeneity and aid diagnostic and prevention strategies through improved understanding of gene-environment interactions. To this end, mouse models have been developed to isolate the influences of individual genetic lesions in the context of consistent genotypes and environmental exposures. However, the extent of normal prostatic phenotypic variability dictated by a genetic background potentially capable of influencing the process of carcinogenesis has not been established. In this study we used microarray analysis to quantitate transcript abundance levels in the prostates of five commonly studied inbred mouse strains. We applied a multiclass response t-test to identify genes whose expression in each strain significantly differed from the other four strains. Approximately 13% (932 genes) exhibited significant differential expression (range 1.3 to 190-fold) in one strain relative to other strains (FDR≤10%). The pattern of variability in transcript levels did not result from variations unique to a particular strain, but rather represented genetic variability across all five strains assessed. Expression differences were confirmed by qRT-PCR, or immunohistochemistry for several genes previously shown to influence cancer progression such as Psca, Mmp7, and Clusterin. Analyses of human prostate transcripts orthologous to variable murine prostate genes identified differences in gene expression in benign epithelium that correlated with the differentiation state of adjacent tumors. For example, the expression of apolipoprotein D, a gene known to enhance resistance to cell stress in Drosophila, was expressed at significantly greater levels in benign epithelium associated with high-grade versus low-grade cancers. These data support the concept that the cellular, tissue, and organismal context contribute to oncogenesis and suggest that a predisposition to a sequence of events leading to pathology may be determined prior to cancer initiation. Keywords: mouse, prostate, transcript, variation, microarray, cancer, apolipoprotein D

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Single cell atlas of epithelial and stromal cell heterogeneity by lobe and strain in the mouse prostate

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