ArticleCancer research2023
Matrix Stiffness Triggers Lipid Metabolic Cross-talk between Tumor and Stromal Cells to Mediate Bevacizumab Resistance in Colorectal Cancer Liver Metastases.
Article in Cancer research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers, 1 of them a synthesis that pooled it.
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Who cites it
68 citing papers in PubMed, 1 synthesis or guideline pooled it, 80 citations in OpenAlex.
- Advances in bevacizumab in colorectal cancer: a bibliometric analysis from 2004 to 2023.Frontiers in oncology · 2025Pooled it
- Integrated Spatial and Bulk Untargeted Metabolomics Characterize Location- and Histology-Associated Metabolic Heterogeneity in Colorectal Cancer.Journal of proteome research · 2026Article
- A Protocol for Colorectal Tumor Spheroid Culture in Tunable Stiffness Alginate-Based Hydrogels and Subsequent Immunohistochemical Analysis.Bio-protocol · 2026Article
- Cancer drug response and resistance: molecular mechanisms and combating strategies.Signal transduction and targeted therapy · 2026Review
- Prognostic analysis and beneficiary population exploration of subsequent treatment regimens after third-generation EGFR-TKIs failure in EGFR-mutated advanced non-small cell lung cancer: a retrospective cohort study.Translational lung cancer research · 2026Article
- Multidrug resistance in cancer: current understandings and future perspective.Molecular biomedicine · 2026Review
- Single-cell and deep learning identify hypoxia-responsive lncRNAs predicting outcomes in colorectal cancer.NPJ precision oncology · 2026Article
- Mechanical regulation of microenvironment remodeling in brain tumors: from mechanism to therapy.Journal of neuroinflammation · 2026Review
- ENO2 drives tumor cell-induced M2 macrophage polarization to promote colorectal cancer liver metastasis.Signal transduction and targeted therapy · 2026Article
- Tumor Anti-Angiogenesis Therapy and Its Influence on Immune Cell Function in the Tumor Microenvironment.Cancer medicine · 2026Review
- Fatty acid metabolic reprogramming in the tumor microenvironment: Unraveling mechanisms and therapeutic prospects.Genes & diseases · 2026Review
- Biomimetic nanodecoys remodel the mechano-immune microenvironment to potentiate checkpoint blockade in colorectal cancer.Journal of nanobiotechnology · 2026Article
- Multiomic and functional validation of ACSL3, a regulator of fatty acid metabolism, as a lymph node metastasis-associated gene in lung adenocarcinoma.Respiratory research · 2026Article
- Smart hydrogels for overcoming cancer multidrug resistance.Molecular cancer · 2026Review
- Liver Stiffness Rises Early in MASLD and Drives Inflammation, Lipid Dysmetabolism, and Fibrosis via Piezo1-YAP Mechanotransduction.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Statistical models to characterize colon tumor stiffness heterogeneity through representative atomic force microscopy maps.Scientific reports · 2026Article
- Review
- Deciphering Stiffness-Driven Changes in Colorectal Cancer by Proteomics.Molecular & cellular proteomics : MCP · 2026Article
- Deubiquitinase OTUD5 facilitates stiffness-induced hepatic stellate cell activation by stabilizing YAP.Molecular and cellular biochemistry · 2026Article
- Association of intratumoral CD68Frontiers in immunology · 2026Article
8 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
14 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.