Patient-derived models reveal LTBP2-linked collagen I niche that prime adaptive cell plasticity and tune chemoresponse in colorectal cancer

Background The extracellular matrix (ECM) is a critical component of the tumour microenvironment (TME) and regulates epithelial plasticity and therapeutic responses in colorectal cancer (CRC). However, the mechanisms by which specific ECM components modulate tumour cell state and chemotherapy response remain poorly understood, and physiologically relevant models to investigate these interactions are limited. Here, we investigated how collagen I-rich ECM regulates epithelial plasticity and chemotherapy responses in CRC using patient-derived organoids (PDOs). Methods CRC PDOs were cultured in collagen I-enriched matrices to model ECM-driven changes in tumour cell state. TGFβ pathway activation, epithelial–mesenchymal transition (EMT)-associated transcriptional programmes and expression of extracellular matrix-associated factors were assessed following collagen I exposure. Collagen I-primed PDOs were subsequently evaluated in xenograft models to determine whether ECM-induced phenotypes were maintained in vivo. Chemotherapy-induced transcriptional responses were assessed in collagen I-rich and control conditions, with pharmacological inhibition of TGFβ or p38 signalling used to investigate pathway dependence. Results Collagen I-enriched matrices induced robust TGFβ signalling and increased expression of the secreted extracellular protein LTBP2, accompanied by a partial EMT-associated transcriptional programme in CRC PDOs. Collagen I-primed xenografts developed EMT-biased, LTBP2-high tumours with increased TGFβ pathway activation, supporting the persistence of ECM-induced cellular states in vivo. Furthermore, exposure to a collagen I-rich environment markedly enhanced the pro-inflammatory transcriptional response to chemotherapy. Pharmacological inhibition of TGFβ or p38 signalling modulated this chemotherapy-induced inflammatory programme, implicating these pathways in ECM-dependent adaptive responses. Conclusions Our findings demonstrate that collagen I-rich ECM establishes a distinct tumour microenvironmental niche that promotes TGFβ-dependent EMT priming, epithelial plasticity and altered chemotherapy responses in CRC. Collagen I-enriched PDO models provide a physiologically relevant platform to investigate ECM–tumour interactions and identify mechanisms underlying microenvironment-driven therapeutic adaptation. These findings provide a mechanistic framework linking ECM composition to tumour cell plasticity and treatment response and support further investigation of TGFβ and p38 signalling as potential strategies to overcome ECM-mediated treatment resistance.