Cancer-driven neutrophil priming couples systemic epithelial regenerative programs with pre-metastatic niche formation

Cancer progression involves systemic changes that extend beyond the primary tumour. Through cancer-induced systemic conditioning, breast tumours generate subclinical alterations in distant organs that facilitate metastatic seeding and pre-metastatic niche formation. Neutrophils, mobilized through cancer-driven emergency granulopoiesis, actively contribute to this process. In this study we extend the concept of neutrophil-dependent conditioning beyond pre-metastatic sites, uncovering a broader systemic regenerative activation that links inflammation, tissue regeneration, and metastasis. This activation manifests as enhanced epithelial progenitor activity, measured by increased organoid formation, across multiple organs, including those with low risk of breast cancer metastasis. This neutrophil-dependent perturbation in lung alveolar progenitors and intestinal epithelial lineage commitment, is an indication of an altered organ physiology, enhancing tissue resilience to injury. Moreover, we identify UPP1 expression, which exclusively characterizes neutrophils generated through emergency granulopoiesis, as a key factor sustaining high translational activity in neutrophil progenitors and enabling the full acquisition of cancer-primed properties. Consequently, neutrophil loss of UPP1 reduces both their lung pro-metastatic function and their capacity to activate alveolar progenitors. Mechanistically, this involves interactions between cancer-primed neutrophils and platelets, which localize within lung interstitial spaces near alveolar cells to stimulate epithelial progenitor activity. Together, these findings uncover a previously unrecognized tumour-induced systemic conditioning in which neutrophils coordinate epithelial regenerative activation as part of a pro-metastatic epithelial niche, with UPP1 as a key determinant of their cancer-primed state.