Remodeling of Colorectal Cancer Extracellular Matrix after Radiotherapy

Colorectal cancer (CRC) is a common and aggressive malignancy with poor prognosis. The efficacy of radiotherapy is often limited by the development of radioresistance, which can be attributed to various factors, including the extracellular matrix (ECM). The effect of radiotherapy on the ECM proteome remains poorly understood. We investigated changes in the proteome composition of CRC tumors after radiation therapy. Quantitative LC-MS/MS analysis of the purified ECM fraction was performed, that was supplemented by transcriptomic analysis of clinical samples obtained from patients after neoadjuvant radiochemotherapy. Radiotherapy markedly increased the number of identified ECM proteins, with the number of identified matrisome proteins rising from 45 to 87. In the irradiation group, 12 proteins showed significant upregulation (FDR-adjusted p < 0.01), with fibrillin-1 (Fbn1) showing the greatest increase (632-fold). Structural ECM components, in particular glycoproteins, constituted the majority of proteins with significantly increased abundance. Transcriptomic analysis confirmed the upregulation of key ECM proteins in clinical samples and their positive correlation with the gene signatures of cancer-associated fibroblasts. We conclude that radiotherapy causes significant remodeling of the CRC ECM with predominant upregulation of structural components, indicating the induction of a fibrotic response. The identified proteins may serve as new biomarkers of the response to radiation and potential targets for overcoming radioresistance in CRC.