THY1+ cancer stem cells drive metastasis through a pseudohypoxic state shaped by neutrophil-derived mitochondria
Menée à l'aide de lignées cellulaires, de modèles murins ainsi que d'échantillons sanguins et d'échantillons tumoraux issus de patients atteints d'un carcinome hépatocellulaire, cette étude met en évidence un mécanisme par lequel une sous-population de cellules souches cancéreuses surexprimant THY1 favorise le processus métastatique via l'acquisition d'un état pseudohypoxique induit par l'internalisation de mitochondries endommagées (riches en espèces réactives de l'oxygène) ayant été expulsées par des neutrophiles après une série d'événements impliquant l'axe THY1-Mac1, la voie de signalisation Src–Akt/Erk et la GTPase Rac1
Whether a distinct subset of cancer stem cells (CSCs) is exclusively responsible for metastasis and how this process occurs remain unresolved. Through multi-omics, pan-cancer analysis and multiple tumour-bearing models, we identify THY1⁺ CSCs as the key drivers of metastasis and uncover a previously unrecognized ‘pseudohypoxic’ state (independent of classical hypoxia) as a central regulatory factor. The self-renewal of THY1⁺ CSCs is maintained by IL-6–MYC signalling. Upon encountering neutrophils, THY1⁺ CSCs activate the THY1–Mac1 axis, triggering the Src–Akt/Erk pathway, Rac1 activation and a migrasome-dependent process that induces neutrophils to expel reactive oxygen species-enriched damaged mitochondria. THY1 signalling further enhances macropinocytosis, enabling CSCs to internalize these mitochondria and adopt a pseudohypoxic state, thereby facilitating CSC metastasis. Notably, targeting the IL-6–Myc, THY1–Mac1 or Src–Akt/Erk signalling pathways effectively suppresses pseudohypoxia-driven CSC metastasis. These findings unveil previously unexplored mechanisms by which CSCs undergo metastasis, offering potential strategies to combat tumour metastasis and improve cancer prognosis.
Nature Cell Biology , article en libre accès, 2026