Resident tissue macrophages transfer selenium transporter protein to protect pancreatic cancer from ferroptosis
Menée notamment à partir de l'analyse du profil génomique à l'échelle cellulaire d'échantillons d'adénocarcinomes canalaires du pancréas, d'une analyse spatiale, d'un traçage de lignées cellulaires et d'un suivi du sélénium, cette étude met en évidence un mécanisme par lequel les macrophages tissulaires résidents situés spécifiquement à la périphérie des tumeurs transfèrent une protéine transportrice du sélénium aux cellules cancéreuses en cours de transition épithélio-mésenchymateuse pour les protéger de la ferroptose
Pancreatic ductal adenocarcinoma (PDAC), an aggressive cancer with a poor prognosis, contains resident tissue macrophages (RTMs) present before tumor onset and monocyte-derived macrophages recruited during tumor development, but their distinct roles in supporting tumor progression remain unclear. Combining single-cell profiling, spatial analysis, lineage tracing, RTM depletion, and selenium tracing, we found that RTMs preferentially localize at the tumor border, where they promote epithelial-mesenchymal transition (EMT), tumor growth, and metastasis. Mechanistically, RTMs transfer the selenium transporter Selenop to EMThi tumor cells through LRP8-dependent uptake, increasing tumor-cell selenium availability, limiting lipid peroxidation, and shielding EMThi tumor cells from ferroptosis. RTM-specific Selenop deletion or tumor-cell Lrp8 disruption reduced EMT and tumor progression, whereas ferroptosis inhibition reversed the effect of RTM depletion. Human PDAC showed border-enriched SEPP1+ RTMs near EMThi tumor cells, suggesting a conserved macrophage-derived selenium niche that supports invasive tumor states and highlighting the potential for targeting RTMs or their secretory factors in PDAC.
Cell , résumé, 2026