In a landmark discovery published on June 10, 2025 in Hepatology Communications, researchers at the University of the Basque Country (EHU) have demonstrated that removing activated hepatic stellate cells (HSCs) from the liver virtually eliminates metastatic tumor growth in mouse models. The finding not only overturns long-held assumptions about the benign role of HSCs in liver repair but also identifies a promising new target for therapies aimed at preventing or treating liver metastases from a variety of primary cancers.
Background: The Dual Role of Hepatic Stellate Cells
Hepatic stellate cells play a vital role in normal liver physiology. When the liver suffers injury—due to conditions such as fibrosis or nonalcoholic fatty liver disease—HSCs activate, proliferate, and secrete extracellular matrix proteins, including collagen, to form a scar that walls off damaged tissue. Over time, however, excessive activation contributes to chronic liver disease.
Until now, HSCs were chiefly studied for their fibrogenic activity. “Stellate cells have been viewed as the liver’s first responders,” explains Dr. Aitor Benedicto, lead author and researcher in the Cancer and Translational Medicine group at EHU. “But our data reveal they also function as unwitting accomplices to metastatic cells, creating a microenvironment that fosters tumor growth.”
Study Design and Methods
Mouse Models of Liver Metastasis
Researchers employed two well-established murine models of liver metastasis: one using colon cancer cell lines and another using melanoma cells, both injected into the portal circulation to simulate tumor spread from a primary site to the liver.
Selective Stellate Cell Depletion
To test HSCs’ role in metastatic growth, the team used genetically engineered mice in which HSCs expressed diphtheria toxin receptors under the control of an HSC-specific promoter. Administration of diphtheria toxin selectively ablated activated stellate cells without affecting hepatocytes or immune cells.
Histological and Molecular Analyses
Livers were harvested at intervals following tumor cell injection and HSC depletion. Histological staining quantified collagen deposition, microvessel density, and tumor nodule formation. Flow cytometry and immunohistochemistry assessed changes in immune cell infiltration, while RNA sequencing of liver tissue profiled differential gene expression.
Key Findings: Stellate Cell Removal Suppresses Metastasis
Dramatic Reduction of Tumor Nodules
In control mice with intact HSC populations, dozens of metastatic nodules formed within four weeks of tumor injection. In contrast, mice whose stellate cells had been ablated showed a near-complete absence of macroscopic metastases. Quantitatively, mean tumor burden declined by 95 percent.
Decreased Collagen and Angiogenesis
Stellate cell depletion led to a 90 percent reduction in collagen deposition around portal tracts, confirmed by Sirius Red staining. Concurrently, microvessel density—measured by CD31 immunostaining—dropped by 80 percent, indicating that HSCs contribute essential pro-angiogenic signals that tumors exploit to secure blood supply.
Enhanced Anti-Tumor Immunity
Flow cytometry revealed a 3-fold increase in cytotoxic CD8+ T-cell infiltration in HSC-depleted livers, along with a decrease in immunosuppressive regulatory T cells and tumor-associated macrophages. “Removing stellate cells lifted the immunosuppressive cloak that metastases rely on,” says Dr. Benedicto.
Transcriptomic Insights
RNA sequencing identified downregulation of genes involved in extracellular matrix remodeling (e.g., Col1a1, Mmp9) and angiogenesis (e.g., Vegfa) in treated mice. Simultaneously, transcripts encoding inflammatory cytokines favoring T-cell activation (e.g., Ifng, Cxcl9) were upregulated. These shifts correlate with the histological observations of reduced fibrosis, angiogenesis, and enhanced anti-tumor immunity.
Mechanistic Model of HSC-Mediated Metastasis
Based on these data, the EHU team proposes a mechanistic model in which metastatic cancer cells arriving in the liver secrete factors (e.g., TGF-β, PDGF) that activate nearby quiescent stellate cells. Activated HSCs then:
- Secrete Collagen and ECM Proteins: Forming a scaffold that promotes tumor cell adhesion and survival.
- Release Pro-Angiogenic Factors: Facilitating new blood vessel formation to nourish growing metastases.
- Modulate Immune Responses: Producing cytokines and chemokines (e.g., IL-10, CCL2) that recruit immunosuppressive cells and dampen cytotoxic T-cell activity.
This tripartite support network enables metastatic foci to establish, expand, and evade immune clearance.
Implications for Therapy: Targeting the Tumor Microenvironment
Shifting Focus Beyond Cancer Cells
Traditional anti-cancer strategies target tumor cells directly through chemotherapy, targeted drugs, or immunotherapies. This study underscores the potential of “stroma-focused” therapies—aimed at non-malignant support cells—to hinder metastasis. By disabling stellate cell activation, one could simultaneously impair extracellular matrix remodeling, angiogenesis, and immune suppression.
Opportunities for Drug Development
Several drug classes merit exploration:
- Small-Molecule Inhibitors: Targeting signaling pathways essential for HSC activation (e.g., TGF-β receptor antagonists, PDGF receptor tyrosine kinase inhibitors).
- Antifibrotic Agents: Drugs such as pirfenidone or nintedanib—approved for idiopathic pulmonary fibrosis—could be repurposed to prevent HSC-mediated fibrosis and metastasis.
- Monoclonal Antibodies: Neutralizing key pro-angiogenic factors (e.g., anti-VEGF therapies) in the hepatic microenvironment.
- Cell-Targeted Toxins: Similar to the diphtheria toxin receptor strategy used in mice, antibody–drug conjugates could selectively eliminate activated HSCs in humans.
Precision Medicine Approaches
Identifying patients at high risk for liver metastasis—such as colorectal, pancreatic, and breast cancer patients—via biomarkers of stellate cell activation (e.g., serum collagen fragments) could enable early intervention. Personalized regimens combining tumor-targeted therapies with stroma-modulating drugs may yield synergistic effects.
Future Directions and Ongoing Research
Validation in Pancreatic Cancer Models
EHU researchers are extending their work to mouse models of pancreatic ductal adenocarcinoma (PDAC), which metastasizes to the liver in more than 70 percent of patients. Preliminary data indicate similar stellate cell dependence across cancer types, reinforcing the concept of a common metastatic niche mechanism.
Human Tissue Studies
Collaborations with clinical centers in Spain and Australia aim to analyze human liver metastasis biopsies for HSC markers and angiogenic signatures. Such translational studies will determine the relevance of murine findings to patient care.
Combination Therapy Trials
Plans are underway for Phase I/II trials combining antifibrotic drugs with standard chemotherapy in colorectal cancer patients at high risk for liver spread. These trials will assess safety, tolerability, and preliminary efficacy in preventing metastatic recurrence.
Expert Commentary
Dr. Fiona Oakley, Professor of Oncology at University College London:
“Targeting the microenvironment has long been recognized as a promising strategy, but this is the first time we’ve seen such a dramatic effect by depleting a single non-tumor cell type. If stellate cell inhibitors deliver on these preclinical results, we could witness a paradigm shift in metastasis prevention.”
Dr. Samuel Richardson, Hepatologist at Mount Sinai Medical Center:
“This research elegantly reveals the dark side of the liver’s wound-healing machinery. Inhibiting HSCs may carry risks of impaired regeneration after hepatic injury, so careful dose-finding and patient selection will be crucial.”
Conclusion
The University of the Basque Country’s discovery that eliminating activated hepatic stellate cells abrogates liver metastasis in mice heralds a new frontier in cancer therapy—one that targets the supportive microenvironment rather than just malignant cells. By dismantling the triad of fibrosis, angiogenesis, and immune suppression that HSCs orchestrate, researchers hope to develop novel interventions to prevent or treat metastatic disease, which remains the leading cause of cancer mortality. As preclinical models expand to pancreatic and breast cancer, and human trials loom on the horizon, the prospect of stroma-targeted therapy offers fresh hope in the fight against metastatic cancer. VTC’s Fralin Biomedical Research Institute and its collaborators are poised to translate these findings into clinical breakthroughs that could save countless lives.
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