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A spatial atlas of colorectal cancer reveals the influence of stromal niches on tumour differentiation

ABSTRACT: Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related mortality. CRC can be classified into DNA mismatch repair proficient (MMRp) and deficient (MMRd) subtypes, with only ~50% of MMRd tumours responding to immunotherapy. Tumour architecture is spatially heterogeneous, ranging from the necrotic core to the invasive front, accompanied by diverse stromal and immune responses that influence tumour progression and treatment outcomes. To explore the spatial organisation of the tumour-immune microenvironment, we profiled the expression of ~1,000 genes in 846,469 cells from 23 tumour and normal tissue samples using the CosMx Spatial Molecular Imager (SMI). Using a custom bioinformatic pipeline, we performed quality control, cell type annotation, identified 9 spatial niches and provide an interactive web application to explore this data. Spatial niches included normal colonic crypts, tumour masses, neutrophil-rich regions, and lymphoid aggregates. Differential gene expression analysis revealed niche-specific changes to chemokine signalling, T cell infiltration and myeloid cell polarisation could either support or inhibit tumours depending on the niche. To expand the analysis, we integrated public single-cell RNA-Seq datasets, identifying increased tumour stemness in samples with higher neutrophil content that appeared to be driven by inflammation-mediated stromal reprogramming. Additionally, samples enriched in lymphoid aggregates, as defined by a spatial lymphoid aggregate signature, displayed heightened interferon signalling and an increased abundance of proliferating B cells. Finally, we identify gene expression patterns that distinguish tumour cells from normal epithelial cells within tumours. Our analysis reveals that many of the most pronounced changes in tumour gene expression originate from alterations in the tumour microenvironment, while also revealing tumour-intrinsic gene expression. By studying the spatial niches of CRC, we reveal niche-specific dynamics that drive tumours through innate stromal signalling and suggest both tumour-specific and stromally-mediated potential therapeutic targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303070 | GEO | 2025/12/09

REPOSITORIES: GEO

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Project description:Hematopoietic stem cells (HSCs) primarily reside in the bone marrow where signals generated by stromal cells regulate their self-renewal, proliferation, and trafficking. Endosteal osteoblasts and perivascular stromal cells including endothelial cells3, CXCL12-abundant reticular (CAR) cells, leptin-receptor positive stromal cells, and nestin-GFP positive mesenchymal progenitors have all been implicated in HSC maintenance. However, it is unclear if specific hematopoietic progenitor cell (HPC) subsets reside in distinct niches defined by the surrounding stromal cells and the regulatory molecules they produce. CXCL12 (stromal-derived factor-1, SDF-1) regulates both HSCs and lymphoid progenitors and is expressed by all of these stromal cell populations. Here, we selectively deleted Cxcl12 from candidate niche stromal cell populations and characterized the effect on HPCs. Deletion of Cxcl12 from mineralizing osteoblasts has no effect on HSCs or lymphoid progenitors. Deletion of Cxcl12 from osterix-expressing stromal cells, which includes CAR cells and osteoblasts, results in constitutive HPC mobilization and a loss of B lymphoid progenitors, but HSC function is normal. Cxcl12 deletion in endothelial cells results in a modest loss of long-term repopulating activity. Strikingly, deletion of Cxcl12 in nestin-negative mesenchymal progenitors using Prx1-Cre is associated with a marked loss of HSCs, long-term repopulating activity, HSC quiescence, and common lymphoid progenitors. These data suggest that osterix-expressing stromal cells comprise a distinct niche that supports B lymphoid progenitors and retains HPC in the bone marrow, while expression of CXCL12 from stromal cells in the perivascular region, including endothelial cells and mesenchymal progenitors, support HSCs. Total of three samples of two groups analyzed. Replica samples of CXCL12-abundant reticular (CAR) cells from two CXCL12-GFP knock-in mice and a combined sample of PDGFRa+ Sca+ CD45- lineage- cells from three Prx1-Cre Rosa26Ai9/+ Cxcl12gfp/+ mice were used and analyzed.

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A spatial atlas of colorectal cancer reveals the influence of stromal niches on tumour differentiation

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