The impact of a high fat diet and platelet activation on pre-metastatic niche formation

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 ()
Additional contact information
Marta Hergueta-Redondo: Spanish National Cancer Research Center (CNIO)
Sara Sánchez-Redondo: Spanish National Cancer Research Center (CNIO)
Begoña Hurtado: Vall d’Hebron Institute of Oncology (VHIO)
Vanesa Santos: Spanish National Cancer Research Center (CNIO)
Manuel Pérez-Martínez: Spanish National Cancer Research Center (CNIO)
Pilar Ximénez- Embún: Spanish National Cancer Research Center (CNIO)
Sheri A. C. McDowell: McGill University
Marina S. Mazariegos: Spanish National Cancer Research Center (CNIO)
Gadea Mata: Spanish National Cancer Research Center (CNIO)
Raúl Torres-Ruiz: Spanish National Cancer Research Center (CNIO)
Sandra Rodríguez-Perales: Spanish National Cancer Research Center (CNIO)
Lola Martínez: Spanish National Cancer Research Center (CNIO)
Osvaldo Graña-Castro: Spanish National Cancer Research Centre (CNIO)
Diego Megias: Spanish National Cancer Research Center (CNIO)
Daniela Quail: McGill University
Miguel Quintela-Fandino: Centro Nacional de Investigaciones Oncológicas
Héctor Peinado: Spanish National Cancer Research Center (CNIO)

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract There is active crosstalk between tumor cells and the tumor microenvironment during metastatic progression, a process that is significantly affected by obesity, particularly in breast cancer. Here we analyze the impact of a high fat diet (HFD) on metastasis, focusing on the role of platelets in the formation of premetastatic niches (PMNs). We find that a HFD provokes pre-activation of platelets and endothelial cells, promoting the formation of PMNs in the lung. These niches are characterized by increased vascular leakiness, platelet activation and overexpression of fibronectin in both platelets and endothelial cells. A HFD promotes interactions between platelets, tumor cells and endothelial cells within PMNs, enhancing tumor cell homing and metastasis. Importantly, therapeutic interventions like anti-platelet antibody administration or a dietary switch reduce metastatic cell homing and outgrowth. Moreover, blocking fibronectin reduces the interaction of tumor cells with endothelial cells. Importantly, when coagulation parameters prior to neoadjuvant treatment are considered, triple negative breast cancer (TNBC) female patients with reduced Partial Thromboplastin time (aPTT) had a significantly shorter time to relapse. These findings highlight how diet and platelet activation in pre-metastatic niches affect tumor cell homing and metastasis, suggesting potential therapeutic interventions and prognostic markers for TNBC patients.

Date: 2025
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DOI: 10.1038/s41467-025-57938-9

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