Abstract In the United States, colorectal cancer (CRC) is the third leading cause of cancer-related deaths in both men and women, with a projected 154,270 new cases in 2025 alone. These statistics highlight the need for a better understanding of the underlying mechanisms of CRC and the development of improved therapies, which are both critical steps in improving patient outcomes. CRC is characterized by extensive stromal cell involvement, which is believed to be tumor-supportive, and thus components of the tumor microenvironment (TME) are promising targets. Collagen triple helix repeat containing 1 (CTHRC1) is a secreted protein with known roles in metabolism, bone and joint homeostasis, tissue remodeling, extracellular matrix synthesis and organization, and, by unknown mechanisms, oncogenesis. Despite its known expression in tumor-associated stroma and correlations with poor prognosis in many cancers, causative evidence that host-derived CTHRC1 influences CRC progression is lacking, and its function within the TME remains poorly understood. Here, we assess the role of host-derived CTHRC1 in three independent in vivo studies using male and female wild-type (WT) and global Cthrc1 null (KO) mice subcutaneously inoculated with MC38 colon cancer cells. Across all studies, our results clearly demonstrate that host-derived CTHRC1 drives CRC progression. Survival analysis showed significant improvement in Cthrc1 KO mice (p = 0.0012, Kaplan-Meier), with median survival more than doubling from 28 days post-inoculation in WT (n = 10) to 69 days in Cthrc1 KO (n = 10). Notably, initial tumor growth followed by tumor regression occurred in all three Cthrc1 KO cohorts between Days 9-14 post-inoculation, while most WT tumors continued growing, suggesting CTHRC1 supports tumor cell immune evasion and contributes to a tumor-permissive TME. Cthrc1 KO mice also developed significantly smaller tumors across all studies compared to WT, as measured by bioluminescent imaging, calipers, and postmortem tumor weights.Histological staining further revealed that the absence of CTHRC1 in the TME alters tumor microarchitecture and cellularity, with tumor density markedly reduced in Cthrc1 KO mice by H Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2267.
Duval et al. (Fri,) studied this question.