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

Abstract

Fat diet; Platelet activation; Pre-metastatic niche formation

Dieta rica en grasas; Activación plaquetaria; Nicho premetastásico

Dieta rica en greixos; Activació plaquetària; Nínxol premetàstic

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.

This work was supported by the Worldwide Cancer Research UK (24-0197, 16-1244), Agencia Estatal de Investigación/Ministerio de Ciencia e Innovación (AEI/MCIN: PID2020-118558RB-I00/AEI/10.13039/501100011033), WHRI-ACADEMY, a COFUND of Marie Curie action (WHRI-309), Fundación Bancaria “la Caixa” (HR18-00256) granted to HP. This work was also supported by grants from the Spanish National Research and Development Plan, Instituto de Salud Carlos III, and FEDER (PI20/01837 and PI23/01932 to S.R-P.); and AECC (AECC_Lab 2020) to S.R-P and ISCIII/FEDER (PI21/01641) to R.T-R. The CNIO is a certified Severo Ochoa Center of Excellence, supported by the Spanish Government through the Instituto de Salud Carlos III (ISCIII). We thank Drs. Cyrus Ghajar, Luuke Hawinkels and Inge Verbrugge for providing cell lines, and we are grateful to Beatriz Salinas (Hospital General Universitario Gregorio Marañon) for synthetizing the NIR-IF dextran. We also thank the CNIO Histopathology Unit for their technical support and Alicia Garcia Arroyo (Centro de Investigaciones Biologicas) for her help in isolating MLECs. Figures were partially created with Servier Medical Art (https://smart.servier.com/) and Adobe Illustrator 24.1.