Microenvironmental CTHRC1 has a pro-tumorigenic role in colorectal cancer

Haylee Duval1,2, Barbara Toomey1, Michelle Karam1,3, Tatum Braun1,4, Daniel Fournier1,5, Chloe Grant1,5, Heather Fairfield1,2,4, Vadim Chepurko1, Elena Chepurko1, Allyson Schimelman1,3, Brian Nestor1,4, Sergey Ryzhov1,2,4, Volkhard Lindner1,2,4 and Michaela R. Reagan1,2,4 1 Center for Molecular Medicine, Maine Health Institute for Research, Scarborough, ME 04074, USA 2 Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME 04469, USA 3 The Roux Institute at Northeastern University, Portland, ME 04101, USA 4 Tufts University School of Medicine, Boston, MA 02111, USA 5 Department of Biological Sciences, University of Southern Maine, Portland, ME 04103, USA Correspondence to: Sergey Ryzhov, email:Sergey.Ryzhov@mainehealth.org Volkhard Lindner, email:Volkhard.Lindner@mainehealth.org Michaela R. Reagan, email:Michaela.Reagan@mainehealth.org Keywords: Cthrc1; CRC; colorectal cancer; subcutaneous tumor model; immune analysis Received: January 07, 2026     Accepted: April 30, 2026     Published: May 20, 2026 Copyright: © 2026 Duval et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Collagen triple helix repeat containing 1 (CTHRC1) is a secreted protein that has previously been explored for its role in tissue remodeling and cancer. However, its function in the tumor microenvironment (TME) remains poorly understood, despite its known expression in tumor-associated stroma. Colorectal cancer (CRC), a malignancy characterized by extensive stromal involvement, poses an excellent opportunity to investigate this gap. Here, we provide the first evidence that host-derived CTHRC1 drives colon cancer progression, with this effect consistently observed across three independent cohorts. Specifically, when injected with CRC cells, Cthrc1 null (global knockout, KO) mice develop significantly smaller and less dense tumors compared to wild-type (WT) mice. Additionally, median survival increased approximately 2.5-fold in Cthrc1 KO mice, from 28 days post-inoculation in WT (n = 10) to 69 days in CTHRC1-deficient mice (n = 10), suggesting CTHRC1 promotes tumor growth within the TME. Immune cell profiling revealed differences in the composition of tumors and spleens of these mice; specifically, Cthrc1 KO mice exhibited an increased percentage of CD3+ T cells in both tumors and spleens and decreased Gr-1+ myeloid cells in the spleen, compared to WT, indicating an immunoregulatory role for CTHRC1 in CRC. These results identify CTHRC1 as a key driver of CRC that may suppress the immune system, allowing for easier immune evasion by tumor cells, highlighting CTHRC1 as a potential new target for therapy.