CXCL14+ fibroblasts promote development of IBD-associated fibrosis and cancer by interacting with SPP1+ macrophages via collagen IV secretion
Menée à l'aide de modèles murins et à partir de l'analyse transcriptomique et immunohistochimique d'échantillons tissulaires provenant de patients atteints d'une maladie inflammatoire chronique de l'intestin ou d'un cancer colorectal, cette étude met en évidence un mécanisme par lequel les fibroblastes CXCL14+, en recrutant les macrophages SPP1+ via la sécrétion de collagène IV, favorisent la transition entre inflammation intestinale et fibrose ou cancer
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.
British Journal of Cancer , article en libre accès, 2026