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Loss of Mast cells and histaminergic signaling link diet to platelet-mediated NETosis and mammary cancer recurrence
Preprint   Open access

Loss of Mast cells and histaminergic signaling link diet to platelet-mediated NETosis and mammary cancer recurrence

Claire P. Schane, Adam T. Nelczyk, Cheng Chen, Jiyoung Seo, Yu Wang, Natalia Krawczynska, Shruti V. Bendre, Erin Weisser, Dhanya Pradeep, Hashni Epa Vidana Gamage, …
bioRxiv
Cold Spring Harbor Laboratory Preprints
04/15/2026
DOI: 10.64898/2026.04.14.718388
PMID: 42039449
url
https://doi.org/10.64898/2026.04.14.718388View
Preprint (Author's original) This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Breast cancer recurrence remains a clinical challenge. The period after the treatment of the primary tumor while cancer cells that evaded initial treatment lay dormant, provides a unique window of opportunity for interventions to prevent recurrence. Specific modifiable factors such as consumption of high fat diets or elevated circulating cholesterol are associated with decreased time to recurrence. Mechanistically, oxidized cholesterol and lipid species have been implicated in the regulation of the tumor microenvironment. This suggests that consumption of food prepared under oxidizing conditions such as pan-frying, may be an underappreciated risk. Using murine models of mammary cancer dormancy, we found that a diet enriched with fat from fried, cured bacon (cfBF) decreased dormancy latency times. Resulting lesions had fewer mast cells (MCs). Loss of MCs alone resulted in reemergence from dormancy. Elevated expression of a MC gene signature in breast tumors was associated with improved progression free and overall survival, highlighting the human relevance of these findings. MCs are a major source of tissue histamine, and lesions from mice fed cfBF had decreased concentrations. Importantly, antagonists of the histamine receptor 2 (H 2 R) sparked reemergence from dormancy. H 2 R antagonists are over-the-counter drugs are taken to alleviate gastroesophageal reflux disease. Chronic treatment of mice with H 2 R-antagonists sensitized platelets towards activation and crosstalk with neutrophils, and subsequent formation of neutrophil extracellular traps (NETs). The loss of platelet or NETosis activity mitigated the H 2 R-antagonist stimulated reemergence from dormancy. Therefore, we establish a novel metastatic axis which links diet to recurrence via MCs, histaminergic signaling and NETosis: Diet – MC – H 2 R – ( decreased ) Platelet Activity – ( decreased ) Neutrophil-NETosis – ( decreased ) Reemergence from Dormancy. Our data reveal several potential intervention strategies: lifestyle, MC stabilization, histaminergic signaling, and neutrophil and platelet activity.

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