Inhibition of ACVR1 in Cancer-Associated Fibroblasts Suppresses Colorectal Cancer Cell Growth

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BACKGROUND: Colorectal cancer (CRC) is the third most common malignancy worldwide and a leading cause of cancer-related mortality. Stromal signatures in CRC are correlated with poor prognosis and resistance to chemotherapy, affecting tumor progression and relapse. Although single-cell analyses have identified subpopulations of cancer-associated fibroblasts (CAFs), effective molecular targeted therapies against CAFs are lacking. MATERIALS AND METHODS: We employed organoid culture methods, focusing on two-dimensional organoids (2DOs) to mimic CRC histology. Using single-cell analysis, we investigated cancer-fibroblast crosstalk, with emphasis on activin receptor type I (ACVR1) in fibroblasts and bone morphogenetic protein 7 (BMP7) in cancer cells as potential therapeutic targets. The correlation between high ACVR1 and BMP7 expression levels and the prognosis of patients with stage II cancer was evaluated. RESULTS: The 2DO mouse xenograft model replicated the characteristics of the fibroblast subpopulations present in human CRC tumors. Single-cell RNA sequencing identified fibroblast clusters, with the BMP7-ACVR1 axis emerging as a potential therapeutic target. High BMP7 and ACVR1 expression was significantly correlated with poor disease-free survival and overall survival in stage II CRC. Administration of an ACVR1 inhibitor during the coculture of 2DOs and mouse stromal cells inhibited tumor growth. CONCLUSIONS: ACVR1 is a promising therapeutic target that inhibits CAF proliferation. High BMP7 and ACVR1 expression is a significant prognostic factor in stage II CRC.

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