Adipose myostatin mediates lipid signaling from obese adipose tissue to tumors

Obesity is more than just extra weight; it is a state where the body's fat tissue becomes chemically active in ways that can harm other organs. For decades, scientists have known that people with obesity face a higher risk of developing cancer and that tumors often grow faster in these individuals. The fat tissue surrounding tumors is not merely a passive storage depot. Instead, it acts like a chemical factory, releasing fatty acids and signaling molecules into the bloodstream. These substances can travel to distant sites, including tumors, where they may serve as fuel or send instructions that encourage the cancer to spread. However, the specific chain of events that connects the dysfunction of fat tissue to the aggressive behavior of a tumor has remained a mystery. Understanding this link is crucial because it could reveal new ways to interrupt the communication between fat and cancer, potentially slowing disease progression without directly attacking the tumor itself.

A team of researchers at Fudan University and other institutions has now traced a direct line of communication from fat cells to cancer cells, identifying a specific protein and a specific fat molecule that work together to drive tumor growth in obese individuals. They discovered that a protein called myostatin, which is usually thought of as a regulator of muscle size, plays a hidden and critical role inside fat cells. In mice with obesity, this protein does not just sit idle; it triggers a chain reaction that leads the fat cells to produce a specific type of fatty acid. This fatty acid then travels through the blood to the tumor, where it binds to a key protein inside the cancer cells, effectively flipping a switch that tells the tumor to grow faster and spread.

The researchers began by testing a long-held assumption: that the myostatin driving this process comes from muscle. Since muscle is the primary source of myostatin in the body, it seemed logical that muscle-derived myostatin would be the culprit. To test this, they created mice that lacked myostatin only in their muscles. When these mice were fed a high-fat diet to induce obesity and then given cancer cells, the tumors grew just as fast as they did in normal obese mice. This result ruled out muscle as the source of the problem. The team then turned their attention to the fat tissue itself. They created a second group of mice that lacked myostatin only in their fat cells. In these animals, the high-fat diet still caused obesity, but the tumors grew significantly slower, and the mice survived longer. This finding pinpointed the fat cell as the true origin of the signal that fuels the cancer.

To understand how a fat cell lacking myostatin could slow down a tumor, the scientists looked at what these cells were releasing into the blood. They found that when myostatin is present in fat cells, it triggers the production of an enzyme that converts a common fatty acid into a different, unsaturated one called palmitoleic acid. In the mice with myostatin in their fat cells, levels of this palmitoleic acid were high. In the mice without it, levels were low. When the researchers applied the liquid from the fat cells of normal mice to cancer cells in a dish, the cancer cells grew rapidly. However, when they used liquid from the fat cells of the modified mice, the cancer cells grew much more slowly. This confirmed that the fat cells were sending a chemical message, and that message depended on the presence of myostatin.

The next step was to identify the receiver of this message inside the cancer cells. The researchers suspected that the palmitoleic acid was not just acting as food but as a direct signal. They used a probe to catch any proteins in the cancer cells that would bind to this fatty acid. The probe latched onto a protein called pyruvate kinase M2, or PKM2 for short. This protein is known to be involved in how cells process energy, but it also has a role in controlling which genes are turned on. The team found that when palmitoleic acid attached to PKM2, it caused the protein to change its shape and move from the center of the cell into the nucleus, where it could activate genes that promote tumor growth. When they blocked this movement or prevented the fatty acid from binding to the protein, the cancer cells stopped growing as aggressively.

To prove that this specific pathway was the missing link, the researchers performed a final, decisive experiment. They took the mice that had been genetically modified to lack myostatin in their fat cells—mice that were naturally resistant to fast tumor growth—and gave them extra palmitoleic acid. The result was immediate: the tumors in these mice began to grow rapidly again, returning to the size and speed seen in normal obese mice. This demonstrated that the fatty acid was indeed the functional messenger. Without the myostatin in the fat cells, the fatty acid was not produced, and the tumor could not receive the growth signal. But once the fatty acid was reintroduced, the signal was restored, and the tumor resumed its aggressive behavior.

The study also looked at human data to see if this mechanism might apply to people. They examined tissue samples from patients with cancer and found that the levels of the enzyme responsible for making palmitoleic acid were higher in the fat tissue of cancer patients compared to healthy individuals. Furthermore, they reviewed existing medical studies and found that higher levels of this fatty acid in the blood or tissue were often associated with more aggressive cancers and poorer outcomes in patients with various types of tumors. While these human observations do not prove cause and effect on their own, they align perfectly with the experimental results in mice, suggesting that this pathway is a real and significant factor in human disease.

This research reshapes our understanding of how obesity fuels cancer. It shows that the danger of excess fat is not just about having more fuel available for a tumor to burn. Instead, the fat tissue itself becomes a source of active signals that instruct the tumor to grow. The study identifies a specific molecular circuit: a protein inside the fat cell triggers the creation of a fatty acid, which travels to the tumor and binds to a specific protein to turn on growth programs. By mapping this path, the scientists have revealed a new potential target for therapy. If doctors could block the production of this fatty acid or prevent it from binding to the cancer cell, they might be able to slow down tumor growth in obese patients without needing to target the tumor directly. The work highlights that the body's systems are deeply interconnected, where a change in one tissue can send a chemical command to another, with profound consequences for health.