Collagen Scaffold in Tumors Primes Colorectal Cancer Cells to Evade Chemotherapy

Colorectal cancer remains one of the most common and lethal malignancies worldwide, and while chemotherapy regimens such as 5-fluorouracil have improved survival for many patients, resistance continues to undermine treatment outcomes. A new study published in the Journal of Experimental & Clinical Cancer Research offers a striking explanation for why some tumors fail to respond: the physical scaffolding that surrounds cancer cells may be actively teaching them how to adapt. An international team led by Paloma Ordóñez-Morán at the University of Nottingham, working with collaborators in Belgium, Switzerland, the United Kingdom and industry, has shown that a collagen I-rich extracellular matrix can reprogram colorectal cancer cells into a more plastic, inflammation-prone state that alters their response to chemotherapy.

The extracellular matrix, long dismissed as little more than biological mortar, has increasingly been recognized as an active participant in tumor biology. In colorectal cancer, the matrix is often remodeled and enriched with fibrillar collagens, creating a dense, stiff environment that can influence how cells sense their surroundings. The Nottingham-led team began by mining publicly available transcriptomic datasets from colorectal cancer patients, including GSE44861 and GSE32323, and found that collagen-associated genes, particularly COL1A1 and COL1A2, which encode the alpha chains of type I collagen, were consistently upregulated in tumors compared with healthy tissue. Immunofluorescence staining of patient tumors confirmed frequent accumulation of collagen I in the tumor microenvironment, and Kaplan-Meier survival analysis linked high collagen I signaling to poorer patient outcomes.

To interrogate these correlations experimentally, the researchers turned to patient-derived organoids, miniature three-dimensional tumor cultures grown from surgical biopsies obtained at Queen’s Medical Centre in Nottingham with ethical approval and patient consent. These organoids preserve the genetic and epigenetic identity of the original tumors, including canonical colorectal cancer alterations such as APC, KRAS and TP53 mutations, making them far more faithful than conventional cell lines. The team embedded organoids in a mixed Matrigel-collagen I matrix, designated MGCOL, and compared them with organoids grown in standard Matrigel alone. Two-photon microscopy using second harmonic generation allowed the researchers to visualize the collagen fibers directly within the living gels, while rheological measurements tracked the mechanical properties of the matrices over nearly a month of culture.

The results were unambiguous. When colorectal cancer organoids were grown in collagen I-enriched matrices, they mounted a robust activation of transforming growth factor beta signaling, a master pathway controlling tissue repair, cell identity and immune modulation. Alongside this, the cells increased their expression of LTBP2, latent transforming growth factor-beta binding protein 2, a secreted extracellular protein that sequesters and regulates TGFβ family ligands. The organoids also activated a partial epithelial-to-mesenchymal transition program, a transcriptional shift in which epithelial cells acquire mesenchymal traits such as motility, invasiveness and stress resistance, without fully abandoning their epithelial character. This partial EMT state is increasingly viewed as a hallmark of aggressive, treatment-refractory tumors.

Crucially, the researchers wanted to know whether these matrix-induced changes would persist once cells left the dish. They transplanted collagen I-primed organoids into xenograft mouse models and found that the resulting tumors retained an EMT-biased, LTBP2-high phenotype with elevated TGFβ pathway activation, as measured by phosphorylated SMAD2 staining. This persistence in vivo suggests that the extracellular matrix does not merely produce transient, reversible changes but can lock tumor cells into alternative identity states that survive transplantation. The finding carries significant implications, because it implies that the matrix composition of a patient’s tumor could pre-condition cancer cells before any drug is administered.

The clinical relevance of the LTBP2 signature was reinforced by analysis of The Cancer Genome Atlas colon adenocarcinoma cohort. LTBP2 expression was significantly elevated in metastatic colorectal cancer compared with primary tumors and healthy colon, and high LTBP2 expression was associated with worse disease-free survival across more than 1,300 patients, with a hazard ratio of 1.41. INHBA, another TGFβ pathway component induced by collagen I, showed an even stronger association, with a hazard ratio of 2.48. LTBP2 expression also correlated strongly with FBN1 and LOXL1, genes involved in elastic fiber assembly and collagen cross-linking, tying the LTBP2 signal directly to matrix remodeling biology.

Perhaps the most consequential discovery concerned chemotherapy. When the researchers treated collagen I-primed and control organoids with 5-fluorouracil, the standard backbone drug for colorectal cancer, the collagen-rich environment markedly enhanced the pro-inflammatory transcriptional response to the drug. Cells in collagen I-rich matrices responded to chemotherapy by ramping up inflammatory signaling programs, including chemokine expression, rather than simply undergoing cell death. Pharmacological inhibition of TGFβ signaling using the TGFβ receptor 1 inhibitor SB431542, or of p38 MAPK signaling using SB202190, modulated this chemotherapy-induced inflammatory program, implicating both pathways as mechanistic links between the matrix and the drug response. In other words, the same scaffold that primes cells toward plasticity also tunes how they react when attacked by cytotoxic therapy.

The authors propose that collagen I establishes a distinct tumor microenvironmental niche in which TGFβ-dependent EMT priming, epithelial plasticity and altered chemotherapy responses converge. Rather than a single driver mutation or a single signaling pathway, treatment resistance may emerge from the interplay between a tumor’s genetic identity and the physical and biochemical properties of its surroundings. This mechanistic framework helps explain why patients with histologically similar tumors can respond so differently to identical regimens, and it suggests that matrix composition, measurable through staining or imaging approaches such as Picrosirius red and second harmonic generation, could serve as a biomarker for treatment stratification.

The study also validates collagen I-enriched organoid cultures as a physiologically relevant platform for studying matrix-tumor interactions, something that standard Matrigel cultures, which lack the fibrillar collagen architecture of real tumors, cannot fully capture. By adjusting matrix composition in a controlled way, researchers can now dissect how individual matrix components shape cell state and drug sensitivity in patient-specific backgrounds. The work was supported by the Medical Research Council, the Royal Society and Research Foundation Flanders, and the authors note that the findings support further investigation of TGFβ and p38 signaling as potential therapeutic targets to overcome matrix-mediated treatment resistance.

For patients, the message is that the terrain around a tumor matters as much as the tumor itself. If collagen I-rich niches prime cancer cells to adapt and inflame rather than die under chemotherapy pressure, then combination strategies that target the matrix or its downstream signaling could sensitize tumors that would otherwise resist treatment. While the research remains at the preclinical stage, resting on organoid and xenograft models rather than clinical trials, it adds colorectal cancer to the growing list of malignancies in which the extracellular matrix is emerging as an active architect of therapeutic failure, and it hands clinicians and drug developers a concrete set of molecular handles, LTBP2, TGFβ and p38, with which to intervene.

Subject of Research: Collagen I-driven extracellular matrix regulation of epithelial plasticity and chemotherapy response in colorectal cancer

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

Article References: Sagadevan, S., Dalleywater, W., Balasubramanian, B., Okkelman, I. A., Martinez-Espuga, M., Norkin, M., Gall, L., Mendonca, T., Mukherjee, A., Wright, A. J., Dmitriev, R. I., Acheson, A. G., Huelsken, J., Mata, A., Pin, C., & Ordóñez-Morán, P. (2026). Patient-derived models reveal LTBP2-linked collagen I niche that prime adaptive cell plasticity and tune chemoresponse in colorectal cancer. Journal of Experimental & Clinical Cancer Research. https://doi.org/10.1186/s13046-026-03845-w

Image Credits: AI Generated

DOI: 10.1186/s13046-026-03845-w

Keywords: colorectal cancer, collagen I, extracellular matrix, LTBP2, TGF-beta, patient-derived organoids, epithelial-mesenchymal transition, cell plasticity, chemotherapy resistance, 5-fluorouracil, p38 MAPK, tumor microenvironment