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

Abstract

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. 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. 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. ACVR1 is a promising therapeutic target that inhibits CAF proliferation. High BMP7 and ACVR1 expression is a significant prognostic factor in stage II CRC.