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Spatially distinct reprogramming of the tumor microenvironment based on tumor invasion in diffuse-type gastric cancers

ABSTRACT: The invasive potential of gastric cancers (GCs) defines the hallmarks of malignancies; however, the cellular components and their molecular features associated with tumor invasiveness in GC microenvironments (TME) are poorly understood. In this study, we constructed a comprehensive atlas of 23,060 single cells obtained from surgically dissected superficial and deep layers of five diffuse-type GC along with matched normal. As a result, seven major cell types were identified. Fibroblasts, endothelial cells, and myeloid cells were categorized as being enriched in the deep layers. Cell type-specific clustering further revealed that the superficial-to-deep layer transition is associated with enrichment in inflammatory endothelial cells and fibroblasts with upregulated CCL2 transcripts. This study reveals the spatial reprogramming of the TME that may underlie invasive tumor potential in diffuse-type GC. This TME profiling across tumor layers suggests new targets, such as CCL2, that can modify the TME to inhibit tumor progression in diffuse-type GC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE167297 | GEO | 2021/08/09

REPOSITORIES: GEO

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Project description:Articular and growth plate cartilage have comparable structures consisting of three distinct layers of chondrocytes, suggesting similar differentiation programs and therefore similar gene expression profiles. To address this hypothesis and to explore transcriptional changes that occur during the onset of articular and growth plate cartilage divergence, we used microdissection of 10-day-old rat proximal tibial epiphyses, microarray analysis, and bioinformatics to compare gene expression profiles in individual layers of articular and growth plate cartilage. We found that many genes that were spatially upregulated in intermediate/deep zone of articular cartilage were also spatially upregulated in resting zone of growth plate cartilage (overlap greater than expected by chance, P < 0.001). Interestingly, superficial zone of articular cartilage showed an expression profile with similarities to both proliferative and hypertrophic zones of growth plate cartilage (P < 0.001 each). Additionally, significant numbers of known proliferative zone markers (3 out of 6) and hypertrophic zone markers (27 out of 126) were spatially upregulated in superficial zone compared to intermediate/deep zone (more than expected by chance, P < 0.001 each). In conclusion, we provide evidence that intermediate/deep zone of articular cartilage has a gene expression profile more similar to resting zone of growth plate cartilage, whereas superficial zone has a gene expression profile more similar to proliferative and hypertrophic zones. 10-day-old rat proximal tibial epiphyses were manually microdissected into articular cartilage superficial (SZ) and intermediate/deep (IDZ) zones and growth plate cartilage resting zone (RZ) for total RNA extraction and hybridization on Affymetrix microarrays. We used 10-day-old animals because, at this age, the secondary ossification center has recently begun to form and divides the epiphysis into articular cartilage distally and growth plate cartilage more centrally. The 4 SZ samples were taken from animals 5-8, respectively, whereas the 4 IDZ and 4 RZ samples were each taken from animals 1-2, 3-4, 5-6, and 7-8, respectively.

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Spatially distinct reprogramming of the tumor microenvironment based on tumor invasion in diffuse-type gastric cancers

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