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Cited by 105Cancer, Lipids, and MetabolismAngiogenesis and VEGF in CancerColorectal Cancer Treatments and Studies

Matrix Stiffness Triggers Lipid Metabolic Cross-talk between Tumor and Stromal Cells to Mediate Bevacizumab Resistance in Colorectal Cancer Liver Metastases

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Zheng, Yannan, Zhou, Rui, Cai, Jianan, Yang, Nanyan, Wen, Zhaowei, Zhang, Zhihua, Sun, Huiying, Huang, Genjie +6 more·2023·Cancer Research
DOI 10.1158/0008-5472.can-23-0025PMC PMC10618741

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Abstract

Bevacizumab is an anti-VEGF monoclonal antibody that plays an important role in the combination treatment of advanced colorectal cancer. However, resistance remains a major hurdle limiting bevacizumab efficacy, highlighting the importance of identifying a mechanism of antiangiogenic therapy resistance. Here, we investigated biophysical properties of the extracellular matrix (ECM) related to metabolic processes and acquired resistance to bevacizumab. Evaluation of paired pre- and posttreatment samples of liver metastases from 20 colorectal cancer patients treated with combination bevacizumab therapy, including 10 responders and 10 nonresponders, indicated that ECM deposition in liver metastases and a highly activated fatty acid oxidation (FAO) pathway were elevated in nonresponders after antiangiogenic therapy compared with responders. In mouse models of liver metastatic colorectal cancer (mCRC), anti-VEGF increased ECM deposition and FAO in colorectal cancer cells, and treatment with the FAO inhibitor etomoxir enhanced the efficacy of antiangiogenic therapy. Hepatic stellate cells (HSC) were essential for matrix stiffness–mediated FAO in colon cancer cells. Matrix stiffness activated lipolysis in HSCs via the focal adhesion kinase (FAK)/yes-associated protein (YAP) pathway, and free fatty acids secreted by HSCs were absorbed as metabolic substrates and activated FAO in colon cancer cells. Suppressing HSC lipolysis using FAK and YAP inhibition enhanced the efficacy of anti-VEGF therapy. Together, these results indicate that bevacizumab-induced ECM remodeling triggers lipid metabolic cross-talk between colon cancer cells and HSCs. This metabolic mechanism of bevacizumab resistance mediated by the physical tumor microenvironment represents a potential therapeutic target for reversing drug resistance. Significance: Extracellular matrix stiffening drives bevacizumab resistance by stimulating hepatic stellate cells to provide fuel for mCRC cells in the liver, indicating a potential metabolism-based therapeutic strategy for overcoming resistance.

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  • Accumulating evidence highlights ECM remodeling and tissue mechanics as active determinants of hepatocyte behavior.

    “accumulating evidence highlights extracellular matrix (ECM) remodeling and tissue mechanics as active determinants of hepatocyte behavior [12, 13, 14, 15, 16].”

    From Liver Stiffness Rises Early in MASLD and Drives Inflammation, Lipid Dysmetabolism, and Fibrosis via Piezo1–YAP Mechanotransduction (2026) · cites this paper as [16]

    The Discussion (page not provided) says ECM remodeling and tumor-associated stiffness affect hepatic stellate cells in liver metastases. The Results section on matrix stiffness and lipolysis likewise reports responses in hepatic stellate cells, not hepatocytes. The source supports a role for tissue mechanics in cell behavior, but not the claim’s specific attribution to hepatocyte behavior. (LLM, conf=0.87)

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Cited by

Sorted by citations

Authors
Zheng, Y., Zhou, R., Cai, J., Yang, N., Wen, Z., Zhang, Z., Sun, H., Huang, G., Guan, Y., Huang, N., Shi, M., Liao, Y., Bin, J., & Liao, W.
Affiliations
Nanfang Hospital (CN)
Corresponding author
Liao, Wangjun
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2023-08-23
Volume
83
Issue
21
Pages
3577-3592
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-23-0025
PMC
PMC10618741
OpenAlex
W4386084830
Cited by
105
References
4
Citations by year
2026: 43 · 2025: 41 · 2024: 21
FWCI
13.38
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Research (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (82073303, 82272635, 82102731)
  • Nanfang Hospital (2019Z025)
  • Natural Science Foundation of Guangdong Province (2022A1515012418)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Keywords
bevacizumab resistance, colorectal liver metastases, extracellular matrix stiffness, fatty acid oxidation, hepatic stellate cells, tumor microenvironment, anti-angiogenic therapy, lipolysis, free fatty acids, etomoxir, tumor-stroma interactions
MeSH terms
Bevacizumab, Animals, Colonic Neoplasms, Humans, Lipids, Liver Neoplasms, Colorectal Neoplasms, Stromal Cells, Mice, Tumor Microenvironment

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