Paracrine iron activates Hopx+ rectal cancer stem cells to display radioresistance

Résumé fourni par la source

• Lineage tracing identifies a radioresistant Hopx + cancer stem cell population in rectal cancer in vivo. • Apoptotic tumor cells cause iron overload in neighbor Hopx + CSCs to mediate a STAT3-dependent pro-survival program. • Hopx + cells are resistant to ferroptosis caused by iron overload via inhibiting de novo lipogenesis. The quiescence-activation transition of cancer stem cells regulated by environmental stimuli has been shown to potentially contribute to cancer maintenance and regrowth after therapy. However, little is known about how the neoplastic niche couples with neighboring signals to control the activation of quiescent rectal cancer stem cells during radiotherapy. Lineage-tracing experiments were performed using Hopx CreERT2 ;Rosa tdTomato mice and organoids to visualize the dynamics and radioresistance of Hopx -expressing cells in vivo. BrdU pulse-chase assays and cell cycle analysis were used to identify whether Hopx + stem cells were label-retaining cells (LRCs). The paracrine pro-survival effect of radiotherapy-induced dying cancer cells on neighboring Hopx + quiescent stem cells was analyzed in the context of both apoptosis and necroptosis blockade. Human rectal cancer organoids and patient-derived xenografts (PDXs) were used to assess the radiotherapy-enhanced efficacy of Hopx targeting. Lineage tracing experiments revealed that Hopx + quiescent stem cell subpopulation exhibited an enhanced regeneration, which functionally drove the recurrence of rectal cancer after irradiation. Mechanistically, iron released from radiotherapy-induced tumor cell death triggered a Stat3-dependent pro-survival program in neighbor-surviving Hopx + quiescent stem cells. Interestingly, we demonstrated activated Hopx + cancer stem cells antagonized ferroptosis that should be caused by iron-overload via the inhibition of de novo lipid synthesis. Collectively, quiescent cancer stem cells could establish a new dependency on anti-apoptotic programs in their dying neighbors. This study highlights targeting and regulating Hopx + quiescent stem cells could be a promising therapeutic approach to overcome the refractoriness of human rectal cancer.

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