2. Academic Validation
  3. Integrin-Mediated TIMP1 Signaling Reprograms Liver Macrophages and Accelerates Colorectal Cancer Metastasis

Integrin-Mediated TIMP1 Signaling Reprograms Liver Macrophages and Accelerates Colorectal Cancer Metastasis

  • Cells. 2025 Dec 23;15(1):29. doi: 10.3390/cells15010029.
Jialiang Liu 1 2,  Liming Zhao 1,  Lin Wang 3,  Guoli Sheng 4,  Pu Cheng 1,  Mingyu Han 5,  Guoxin Li 2,  Zhaoxu Zheng 1
Affiliations

Affiliations

  • 1 Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100020, China.
  • 2 Cancer Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, Beijing 102218, China.
  • 3 The State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100020, China.
  • 4 Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100020, China.
  • 5 Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100020, China.
PMID: 41511313 DOI: 10.3390/cells15010029
Abstract

Background: Colorectal Cancer (CRC) frequently metastasizes to the liver (CRLM), where M2-polarized macrophages shape an immunosuppressive pre-metastatic niche. The molecular cues driving this polarization remain unclear.

Methods and results: Using integrated transcriptomics, patient cohorts, and mouse models, we investigated the role of tissue inhibitor of metalloproteinases-1 (TIMP1) in CRLM. TIMP1 was consistently overexpressed in CRC tissues and associated with poor overall survival. CRC cells secreted TIMP1 into the tumor microenvironment, where it induced M2-like macrophage polarization and increased the expression of immunosuppressive mediators such as CSF1 and IRF4. In vivo, TIMP1 overexpression enhanced, whereas its knockdown reduced, liver metastatic burden. Immune profiling and depletion experiments indicated that these pro-metastatic effects were largely macrophage-dependent. Mechanistically, TIMP1 engaged CD63/β1-integrin on macrophages, activating Akt/mTOR signaling and stabilizing the M2 phenotype.

Conclusions: CRC-derived TIMP1 remodels liver macrophages via the CD63/β1-integrin-AKT/mTOR pathway to promote a hepatic pre-metastatic niche. Pharmacologic inhibition of this signaling axis with the Integrin antagonist cilengitide suppressed macrophage M2 markers and liver colonization in mice, supporting TIMP1-integrin signaling as a potential therapeutic target.

Keywords

M2 macrophage polarization; TIMP1; colorectal cancer; liver metastasis; pre-metastatic niche.

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