Cancer-associated fibroblast secreted DKK1 promotes the immunosuppressive tumor microenvironment and colorectal cancer resistance to chemotherapy

Authors

• Zhijie Yin, University of Kentucky
• Yuning Zhou, University of KentuckyFollow
• Xudong Zhu, University of Kentucky
• Ryan A. Goettl, University of Kentucky
• Chi Wang, University of KentuckyFollow
• Heidi L. Weiss, University of KentuckyFollow
• B. Mark Evers, University of KentuckyFollow
• Qingding Wang, University of KentuckyFollow

Abstract

Chemotherapy is the cornerstone of treatment for colorectal cancer (CRC). However, acquired resistance can lead to a decrease in the efficiency of chemotherapy. Here, we show that cancer-associated fibroblasts (CAFs) play a critical role in acquired resistance to chemotherapy. Treatment with 5-fluorouracil (5-FU), oxaliplatin, or SN38 (an active metabolite of irinotecan) increased DKK1 expression and secretion, activation of MEK/ERK, and upregulation of p53 in CAFs. Knockdown of p53 or inhibition of MEK/ERK blocked the increase in DKK1 expression induced by chemotherapeutic agents in CAFs. Consistently, elevated DKK1 and phospho-ERK levels were found in CAFs isolated from surgically resected samples of patients treated with neoadjuvant therapy compared with non-chemotherapy controls. Treatment with recombinant DKK1 promoted the tumor immunosuppressive functions of CAFs, as noted by the increased expression of immunosuppressive cytokines and chemokines. Administration of 5-FU in vivo increased DKK1 levels in the plasma. Treatment with anti-DKK1 neutralizing antibody blocked 5-FU increased DKK1, repressed myeloid-derived suppressor cell (MDSC) tumor infiltration, increased NK cell tumor infiltration, and concurrently enhanced the antitumor efficacy of 5-FU. The current study identified CAF-secreted DKK1 as a contributing factor to chemotherapy resistance. Importantly, our findings provide evidence for targeting DKK1 to counteract chemotherapy resistance in CRC.

Document Type

Article

Publication Date

2025

Notes/Citation Information

0304-3835/© 2025 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.canlet.2025.218060

Funding Information

This work was supported by National Institutes of Health grants R01 CA272669 (to QW and BME), R01 DK48498 (to BME), and P30 CA177558 (to BME).

Repository Citation

Yin, Zhijie; Zhou, Yuning; Zhu, Xudong; Goettl, Ryan A.; Wang, Chi; Weiss, Heidi L.; Evers, B. Mark; and Wang, Qingding, "Cancer-associated fibroblast secreted DKK1 promotes the immunosuppressive tumor microenvironment and colorectal cancer resistance to chemotherapy" (2025). Markey Cancer Center Faculty Publications. 488.
https://uknowledge.uky.edu/markey_facpub/488