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Pre-cancerous Niche Remodelling Dictates Nascent Tumour Persistence

ABSTRACT: Interactions between mutant cells and their environment play a key role in determining cancer susceptibility. However, our understanding of how the pre-cancerous microenvironment contributes to early tumorigenesis remains limited. Here, we show that newly emerging tumours at their most incipient stages shape their microenvironment in a critical process that determines their survival. Analysis of nascent squamous tumours in the upper gastrointestinal tract of the mouse reveals that the stress response of early tumour cells instructs the underlying mesenchyme to form a supportive “pre-cancerous niche”, which dictates the long-term outcome of epithelial lesions. Stimulated fibroblasts beneath emerging tumours activate a wound healing response that triggers a dramatic remodelling of the underlying extracellular matrix, resulting in the formation of a fibronectin-rich stromal scaffold that promotes tumour growth. Functional heterotypic 3D culture assays and in vivo grafting experiments, combining carcinogen-free healthy epithelium and tumour derived stroma, demonstrate that the pre-cancerous niche alone is sufficient to confer tumour properties to normal epithelial cells. We propose a model where both mutations and the stromal response to genetic stress together define the likelihood of early tumours to persist and progress towards more advanced disease stages.

ORGANISM(S): Mus musculus

PROVIDER: GSE271962 | GEO | 2025/12/23

REPOSITORIES: GEO

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Project description: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.

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Pre-cancerous Niche Remodelling Dictates Nascent Tumour Persistence

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