3097 - Iron Released from Radiation-Induced Apoptotic Cells Activates Neighboring Quiescent Colorectal Cancer Stem Cells to Display Radioresistance

05:00pm - 06:00pm PT

Hall F

Screen: 24

POSTER

Presenter(s)

Xiangjun Liu, - Sichuan Cancer Center, Chengdu,

X. Liu¹, S. Wang², D. Liu¹, and J. Lang^2,3; ¹Sichuan Cancer Center, Chengdu, China, ²Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China, ³Sichuan Cancer Hospital and Research Institute, University of Electronic Science and Technology of China, Chengdu, China, Chengdu, China

Purpose/Objective(s):

Emerging studies have shown that the pre-presence of dormant cancer stem cells (CSCs) clones surviving drug treatment is a critical driver of cancer relapse and recurrence upon drug removal. Nevertheless, owing to the lack of lineage tracing experiments, less clear is whether cells with such extensive phenotypic heterogeneity and plasticity can truly represent a therapy-tolerant stem cell that gives rise to cancer regrowth. The transition of CSCs from quiescence to active status is intricately controlled by complex environmental stimuli. However, little is known about how the neoplastic niche couples with neighboring signals to control the activation of quiescent colorectal cancer (CRC) stem cells during radiotherapy.

Materials/Methods:

Using Hopx-CreERT2/Rosa-LSL-tdTomato mice and organoids, we performed lineage-tracing experiments to visualize the dynamics and radioresistance of Hopx-expressing cells in vivo and ex vivo. BrdU pulse-chase assays and cell cycle analysis were used to identify whether Hopx⁺ stem cells were label-retaining cells (LRCs). The paracrined pro-survival effect of radiotherapy-induced apoptotic cancer cells on neighboring Hopx⁺ quiescent CRC stem cells was analyzed in the context of both apoptosis and necroptosis blockade. Human CRC organoids and patient-derived xenografts (PDXs) were used to assess the radiotherapy-enhanced efficacy of Hopx targeting.

Results:

We identified a radioresistance-associated regenerative stem cell subpopulation labeled by Hopx expression in mouse CRC models via leveraging genetic lineage tracing experiments. And it was found that the identified Hopx⁺ population displayed a quiescent cell cycle state in homeostasis via label-retaining assays. Notably, Hopx⁺ quiescent CRC stem cells were significantly activated by radiotherapy to participate in the CRC regrowth process. Furthermore, we demonstrated that radiotherapy-induced tumor cell apoptosis in CRC causes iron release, initiating a Stat3-dependent pro-survival program in neighboring Hopx⁺ quiescent cancer cells.

Conclusion:

Collectively, quiescent Hopx⁺ CRC 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 colorectal cancer. Considering that there are no effective small-molecule inhibitors that selectively target HOPX, regulating iron may be an alternative strategy that is applicable to CRC or other tumor types that highly express HOPX.