CNIO researchers found that in mice on high-fat diets, cancer cells in the bloodstream use platelets as a protective shield, aiding their spread. This fatty diet also makes it easier for tumor cells to settle in other organs and form metastases. The findings suggest future cancer treatments could combine dietary changes with platelet activity control.
Obesity is linked to a higher risk of developing breast cancer, as well as a greater likelihood that the cancer will spread to other organs, a process known as metastasis. However, the underlying biological mechanisms behind this connection have remained unclear.
Now, researchers at the Spanish National Cancer Research Center (CNIO) have uncovered new evidence showing that a high-fat diet can activate biological processes that promote metastasis. The study, led by Héctor Peinado, head of CNIO’s Microenvironment and Metastasis Group, was conducted in animal models of triple-negative breast cancer that typically spread to the lungs. The findings were published in Nature Communications.
For cancer cells to metastasize, they must leave the primary tumor, circulate through the bloodstream, and establish themselves in a new organ. Sometimes, the original tumor sends out molecular signals that alter distant organs in advance, creating a favorable environment, known as a premetastatic niche, for incoming tumor cells to grow.
The CNIO team found that mice made obese through a high-fat diet developed biological changes that supported the formation of a premetastatic niche in the lungs. These changes included increased platelet activation and blood clotting, along with the activation of fibronectin, a protein that helps bind cells in lung tissue, making the lungs more hospitable to metastatic cancer cells.
A platelet armor
It is an established fact that obesity promotes blood clotting, a process that depends on blood cells called platelets. Indeed, as CNIO researcher and first author of the study Marta Hergueta observed, in animals fed with high fat, the cells that are shed from the primary tumor are surrounded, during their journey through the blood, by more platelets than in mice with a normal diet.
One hypothesis is that the platelets could be making it difficult for the body’s defenses to detect the cancer cells: the platelets would form “an armor around the tumor cells, preventing the immune system from recognizing and eliminating them,” explains Peinado.
Fertile breeding ground for metastasis
In addition to affecting platelets, the CNIO group found that the high-fat diet increases the expression of the protein fibronectin in the lung tissue where tumor cells metastasize.
Fibronectin builds the tissue that connects lung cells, thus facilitating the creation of the premetastatic niche that hosts the tumor cell. It also enables the tumor cell to interact more efficiently with platelets. “We have seen that the interaction of the tumor cell with both the lung endothelium and the platelet is regulated by fibronectin,” says Peinado.
Studies in patients
To study the implications of these results for human patients, the CNIO’s Breast Cancer Clinical Research Unit, directed by Miguel Ángel Quintela, participated in the study.
After analyzing blood samples from triple-negative breast cancer patients, obtained before surgery and after undergoing chemotherapy, it could not be verified that obesity posed an additional risk for the generation of metastases. However, patients with increased blood coagulation – with a shorter prothrombin time – were found to have a higher risk of relapse at five years.
These findings “could help identify additional risk factors in breast cancer patients undergoing treatment, thus contributing to a better clinical management of the disease,” says Peinado.
Potential clinical application
The work, carried out in collaboration with other CNIO units and other centers in Spain and Canada, has explored initial avenues for the clinical application of the results. One of them was to modify the diet in animal models. When the high-fat diet was withdrawn, and the mice lost weight, platelet and coagulation behavior returned to normal levels. As a result, metastases were reduced.
“I think these results, coupled with clinical studies from other groups, present a future where dietary intervention or dietary changes, along with control of platelet activity, may increase the efficiency of certain antitumor treatments,” Peinado says. “They are not going to be treatments by themselves, but they can complement them.”
Reference: “The impact of a high fat diet and platelet activation on pre-metastatic niche formation” by Marta Hergueta-Redondo, Sara Sánchez-Redondo, Begoña Hurtado, Vanesa Santos, Manuel Pérez-Martínez, Pilar Ximénez- Embún, Sheri A. C. McDowell, Marina S. Mazariegos, Gadea Mata, Raúl Torres-Ruiz, Sandra Rodríguez-Perales, Lola Martínez, Osvaldo Graña-Castro, Diego Megias, Daniela Quail, Miguel Quintela-Fandino and Héctor Peinado, 2 April 2025, Nature Communications.
DOI: 10.1038/s41467-025-57938-9
This study has been financed mainly by the British NGO Worldwide Cancer Research, in addition to state funds from the Ministry of Science and Innovation, the State Research Agency and the Carlos III Health Institute, as well as European ERDF funds and by private grants from the ‘la Caixa’ Foundation and the Spanish Association Against Cancer (AECC).
