| Autor: |
Li, Christy, Klingler, Stefan, Bodo, Sahra, Jin Cheng, Yan Pan, Adileh, Mohammed, Martin, Maria Laura, Fuller, John, Feldman, Regina, Michel, Adam, Zhigang Zhang, Fuks, Zvi, Kolesnick, Richard |
| Předmět: |
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| Zdroj: |
Cellular Physiology & Biochemistry (Cell Physiol Biochem Press GmbH & Co. KG); 2022, Vol. 56 Issue 4, p436-448, 13p |
| Abstrakt: |
Background/Aims: It is unknown whether cancer stem cells respond differentially to treatment compared with progeny, potentially providing therapeutic vulnerabilities. Our program pioneered use of ultra-high single dose radiotherapy, which cures diverse metastatic diseases at a higher rate (90-95%) than conventional fractionation (~65%). Single dose radiotherapy engages a distinct biology involving microvascular acid sphingomyelinase/ ceramide signaling, which, via NADPH oxidase-2-dependent perfusion defects, initiates an adaptive tumor SUMO Stress Response that globally-inactivates homologous recombination repair of double stand breaks, conferring cure. Accumulating data show diverse stem cells display heightened-dependence on homologous recombination repair to repair resolve double stand breaks. Methods: Here we use colorectal cancer patient-derived xenografts containing logarithmically-increased Lgr5+ stem cells to explore whether optimizing engagement of this acid sphingomyelinase dependent biology enhances stem cell dependent tumor cure. Results: We show radioresistant colorectal cancer patient-derived xenograft CLR27-2 contains radioresistant microvasculature and stem cells, whereas radiosensitive colorectal cancer patient-derived xenograft CLR1-1 contains radiosensitive microvasculature and stem cells. Pharmacologic or gene therapy enhancement of single dose radiotherapyinduced acid sphingomyelinase/ceramide-mediated microvascular dysfunction dramatically sensitizes CLR27-2 homologous recombination repair inactivation, converting Lgr5+ cells from the most resistant to most sensitive patient-derived xenograft population, yielding tumor cure. Conclusion: We posit homologous recombination repair represents a vulnerability determining colorectal cancer stem cell fate, approachable therapeutically using single dose radiotherapy. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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