CXCL14+ fibroblasts promote development of IBD-associated fibrosis and cancer by interacting with SPP1+ macrophages via collagen IV secretion

Abstract

Background The pathogenesis of inflammatory bowel disease (IBD) involves chronic inflammation of the gastrointestinal tract, which predisposes patients to an increased risk of fibrosis and cancer due to prolonged inflammatory stimulation. However, the specific mechanisms underlying secondary gastrointestinal carcinogenesis in individuals with IBD remain poorly elucidated, particularly due to a limited number of studies conducted at single-nuclei level. Methods We investigated the dynamics and interactions of cell subtypes during the progression of IBD-associated cancers through comprehensive analysis including single-nuclei transcriptomics, spatial transcriptomics, ecological dynamic modelling, multiplex immunohistochemistry, in vitro co-culture and in vivo animal studies. Results The results revealed that CXCL14+ fibroblasts, the primary source of collagen in the microenvironment, play a pivotal role in the inflammation-cancer transition. These fibroblasts progressively increase in abundance during this transition and secreted elevated levels of collagen IV. The increased presence of collagen IV promotes the recruitment and differentiation of SPP1+ macrophages. This interaction ultimately contributes to the development and progression of IBD-associated fibrosis and cancer transformation. Collagen IV, secreted by CXCL14+ fibroblasts, plays a pivotal role in promoting the transition from IBD to cancer. Inhibition of collagen IV secretion not only prevents fibrosis but also hinders the development of inflammation-cancer transition. Conclusion Our findings are crucial for understanding the mechanisms underlying IBD-associated cancer and developing innovative therapeutic strategies. During the inflammation-cancer transition, activation of the SOX4 leads to increased COL4A1/A2 secretion by CXCL14+ fibroblasts, resulting in enhanced collagen IV synthesis. Collagen IV binds to ITGB1/CD44 receptors on SPP1+ macrophages and activates EGR1/2 to promote SPP1+ macrophage differentiation, while upregulating S100A10 and ANXA2. Activation of S100A10 and ANXA2 promotes recruitment of SPP1+ macrophages, which contributes to immune escape and secretion of oncogenes, thus further promoting fibrosis and tumorigenesis. In addition, SPP1+ macrophages further stimulate CXCL14+ fibroblasts to secrete COL4A1/A2 via TGF-β1, forming a feedback loop that amplifies interactions in the tumour microenvironment.