The liver, a vital organ for metabolism and detoxification, can be unwittingly transformed into a fertile ground for one of cancer's most aggressive invasions.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating forms of cancer, known for its aggressive nature and resistance to treatment. For the majority of patients, the disease is not discovered until it has already metastasized, or spread to other organs. The liver is the most common site for these secondary tumors, and this liver metastasis is the primary cause of death for pancreatic cancer patients 1 5 .
For years, the question of why pancreatic cancer so efficiently colonizes the liver has puzzled scientists. Traditional research focused on the cancer cells themselves. However, a groundbreaking discovery revealed that the real culprits are not the cancer cells alone, but a group of normal immune cells that are tricked into becoming cancer's accomplices.
This article explores the fascinating and critical role of macrophage-secreted granulin in paving the way for pancreatic cancer to take root in the liver.
The process of metastasis is often described by the "seed and soil" hypothesis. The cancer cells are the "seeds," but they can only grow if they land on a receptive "soil"—a hospitable environment in a distant organ 5 .
Pancreatic cancer cells that break away from the primary tumor and travel through the bloodstream to distant organs.
The liver microenvironment that is preconditioned by cellular accomplices to support metastatic growth.
In pancreatic cancer with liver metastasis, the "soil" is prepared in advance. Researchers found that livers with metastatic tumors are rich with not just cancer cells, but also a supporting cast of immune cells (CD45+), macrophages (CD68+), and activated stellate cells (αSMA+) 2 . This discovery shifted the focus from the seeds to the soil, and specifically, to the cells that prepare it for invasion.
To understand how this betrayal happens, we must first meet the main cellular actors:
These are immune cells recruited from the bone marrow to the liver. They are derived from inflammatory monocytes and are distinct from the liver's resident macrophages, known as Kupffer cells 2 8 . Their primary role is to respond to injury and infection, but in cancer, their abilities are hijacked.
These are the liver's quiet maintenance workers. In a healthy state, they store vitamin A and help maintain the organ's structure. However, when activated, they transform into myofibroblasts—highly active cells that produce large amounts of fibrous tissue, a process similar to scarring 1 .
This is the molecular key to the entire process. Granulin is a protein secreted by MAMs. Under normal circumstances, it is involved in wound healing and tissue repair. In the context of cancer, however, this repair mechanism is co-opted to create a fibrotic, tumor-friendly environment 1 9 .
| Cell or Molecule | Normal Function | Hijacked Role in Cancer |
|---|---|---|
| Metastasis-Associated Macrophages (MAMs) | Immune defense, tissue repair | Recruited by cancer to support metastasis; secrete granulin |
| Hepatic Stellate Cells (hStCs) | Vitamin A storage, tissue structure maintenance | Activated to become myofibroblasts; produce fibrotic scar tissue |
| Granulin | Promotes cell growth, wound healing | Activates stellate cells, driving liver fibrosis that supports tumor growth |
The critical connection between these players was established through a series of elegant experiments, with one landmark study published in Nature Cell Biology providing the clearest evidence 1 2 9 .
| Experimental Approach | Purpose | Key Finding |
|---|---|---|
| Bone Marrow Chimeras | To track the origin of macrophages in the liver | MAMs originate from bone marrow (tdTomato+), not from resident liver cells 2 |
| Genetic Depletion (PI3Kγ-/- mice) | To block the recruitment of inflammatory monocytes | Reduced MAMs led to fewer metastases and less myofibroblast activation 2 |
| Clodronate Liposomes | To chemically deplete macrophages after cancer cells reached the liver | Impaired growth of established metastases and prevented myofibroblast activation 2 |
| Conditioned Media Tests | To study macrophage-stellate cell communication | Media from macrophages activated quiescent stellate cells, an effect lost when granulin was depleted 2 |
Pancreatic cancer cells, either directly or through signals from the developing liver metastasis, send out a call for help. This signal attracts inflammatory monocytes from the bloodstream to the liver 1 2 .
Once in the liver, these monocytes mature into MAMs. These MAMs then begin secreting large amounts of granulin 9 .
The secreted granulin acts on the dormant hepatic stellate cells (hStCs). Upon encountering granulin, the stellate cells undergo a dramatic transformation. They activate, becoming myofibroblasts 1 .
These activated myofibroblasts then secrete other proteins, most notably periostin, which leads to the deposition of a dense, fibrous network around the metastatic tumor cells. This fibrosis creates a stiff, supportive microenvironment that nurtures the cancer cells, allowing them to survive, proliferate, and form full-blown metastatic tumors 1 .
The Proof: When researchers genetically depleted granulin or used drugs to block the recruitment of MAMs, the entire metastatic process was derailed. The stellate cells remained quiet, liver fibrosis was significantly reduced, and pancreatic cancer could not form robust metastases in the liver 1 2 . This confirmed that the MAM-granulin-stellate cell axis is not just a bystander effect, but a critical driver of the disease.
The implications of this research extend beyond laboratory models. In the clinic, doctors have observed that the physical stiffness of the liver is a marker of poor prognosis. A 2023 study measured the elastic modulus (EM)—a precise measure of tissue stiffness—in pancreatic cancer patients with liver metastases 3 .
The findings were striking. Patients with a high "relative EM" (meaning their liver metastases were much stiffer than the surrounding tissue) had significantly worse progression-free survival. In fact, high liver stiffness was an independent predictor of a faster return of the cancer after treatment 3 .
| Clinical Factor | Correlation with High Liver Stiffness (Relative EM) | Statistical Significance (P-value) |
|---|---|---|
| Progression-Free Survival | Shorter survival time | 0.032 3 |
| Size of Liver Metastases | Associated with metastases ≥ 3 cm | 0.007 3 |
| Primary Tumor Location | Correlated with tumor in specific locations | 0.048 3 |
| Presence of Lung Metastasis | More likely to have spread to lungs | 0.040 3 |
This clinical evidence directly supports the laboratory findings: the fibrotic, stiff environment created by activated stellate cells is not just a consequence of the tumor, but an active participant in its aggressive progression.
Unraveling a complex biological process like this requires a diverse array of specialized tools. The following reagents and models were essential in discovering the role of granulin in liver metastasis.
Function: These mice (with mutations in Kras and Trp53 genes) spontaneously develop pancreatic cancer that closely mimics the human disease, including the tendency to metastasize to the liver. They are the gold standard for studying PDAC progression 2 8 .
Function: A "magic bullet" for depleting macrophages. The clodronate drug is packaged into liposomes that are selectively eaten by macrophages, causing their death. This allows researchers to test what happens when MAMs are removed from the equation 2 .
Function: Created by transplanting bone marrow from a donor mouse (e.g., one that produces red fluorescent cells) into an irradiated recipient. This technique allows scientists to distinguish between cells originating from the bone marrow (like MAMs) and the body's resident cells 2 .
Function: This modern technology allows researchers to analyze the gene expression of thousands of individual cells simultaneously. It has revealed an incredible diversity among macrophages in the metastatic liver, identifying specific sub-populations with pro- or anti-tumor functions 8 .
The discovery that macrophage-secreted granulin is a lynchpin in pancreatic cancer liver metastasis has transformed our understanding of this deadly disease. It reveals that cancer's strength lies not only in its own mutations but also in its ability to manipulate the body's normal healing processes for its own benefit.
This research opens up an exciting new frontier for therapy. Instead of targeting the cancer cells alone, which often develop resistance, scientists are now exploring ways to:
By dismantling the supportive network that the cancer relies on, we can hope to make the "soil" of the liver inhospitable, effectively starving the metastatic seeds and preventing them from taking root. For a disease as formidable as pancreatic cancer, this shift in strategy—from attacking the seed to reclaiming the soil—offers a beacon of hope for future treatments.