Neutrophils Physically Interact with Tumor Cells to Promote Breast Cancer

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Merav Cohen , Gray Faculty of Medical and Health Sciences

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Tissues undergo re-organization induced by alterations in cellular composition and aided by intercellular crosstalk involving immune and non-immune cells during development and adulthood. Similarly, remodeling of the tumor microenvironment (TME) during cancer induction and progression is supported by reciprocal signaling between the immune compartment, the tumor cells and the stromal niche. To uncover the tumor-specific pathways driving carcinogenesis, we investigate dynamics in cell state compositions and intercellular molecular communications along the processes of physiological development, homeostasis and carcinogenesis. In the breast tissue, by applying RNA sequencing of single cells and of physically interacting cells (PIC-seq), we identified an exclusive carcinogenic niche, composed of tumor cells, ductal macrophages and vasculature cells. We found that while singlet neutrophils transiently expanded during early physiological development, they were enriched in physical interaction with tumor cells specifically throughout tumor progression. Integrating ligand – receptor and PIC sequencing analyses with various functional experiments unveiled a physical and secreted pro-tumorigenic signaling niche. This approach revealed that neutrophils are recruited by tumor-activated macrophages and physically interact with tumor cells, increasing tumor cell proliferative and invasive properties, as well as endothelial proliferation and angiogenesis. The molecular program upregulated in neutrophil-PICs correlates with lower survival in advanced breast cancer patients. This interaction-driven perspective highlights potential molecular targets and biomarkers for cancer treatment.