Abstract 204: Targeting tumor-stroma interactions: Prognostic and therapeutic implications of the ACVR1-BMP7 axis in colorectal cancer

Abstract The tumor microenvironment plays a critical role in colorectal cancer (CRC) progression, with stromal signatures closely linked to poor prognoses and resistance to chemotherapy. These stromal factors significantly influence tumor dynamics, promoting progression, relapse, and overall worse outcomes. Among these, cancer-associated fibroblasts (CAFs) have gained attention due to their heterogeneity and functional contributions to the tumor microenvironment. Although single-cell analysis has identified distinct CAF subpopulations, molecular-targeted therapies against CAFs remain lacking, highlighting a critical clinical need. To address this, the study utilized organoid culture methods replicating CRC histological architecture. Two-dimensional organoids (2DO) provided a novel platform to study tumor-stromal interactions, facilitating the investigation of cancer-fibroblast crosstalk. The focus was on signaling pathways, specifically the interplay between Activin receptor type I (ACVR1) in fibroblasts and Bone morphogenetic protein 7 (BMP7) in cancer cells, as potential therapeutic targets. Using single-cell analysis and patient-derived models, the study examined the prognostic significance of ACVR1 and BMP7 expression in CRC, especially in stage II patients. Single-cell RNA sequencing identified fibroblast subpopulations, revealing a previously unexplored BMP7-ACVR1 signaling axis. High BMP7 and ACVR1 expression levels were significantly associated with poorer disease-free survival (DFS) and overall survival (OS), emphasizing their prognostic value. Clinical data from stage II patients supported this finding, linking elevated BMP7 and ACVR1 levels to adverse outcomes. The functional role of the BMP7-ACVR1 axis was validated with a 2DO-based mouse xenograft model, which reflected the stromal heterogeneity of human CRC tumors. Tumor growth was significantly inhibited by administering an ACVR1 inhibitor during 2DO-mouse stromal cell co-culture, highlighting the therapeutic potential of targeting ACVR1. This underscores the critical role of CAFs in tumor progression and their potential as therapeutic targets. In conclusion, the study identifies ACVR1 as a promising therapeutic target regulating CAF proliferation, influencing tumor growth and patient outcomes. The prognostic significance of BMP7 and ACVR1 further underscores their potential as biomarkers in stage II CRC. Citation Format: Norikatsu Miyoshi, Shinya Kato, Shiki Fujino, Soichiro Minami, Rie Mizumoto, Rie Hayashi, Kengo Haruma. Targeting tumor-stroma interactions: Prognostic and therapeutic implications of the ACVR1-BMP7 axis in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 204.