Title | Acid Sphingomyelinase-Ceramide Induced Vascular Injury Determines Colorectal Cancer Stem Cell Fate. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Li C, Klingler S, Bodo S, Cheng J, Pan Y, Adileh M, Martin MLaura, Fuller J, Feldman R, Michel A, Zhang Z, Fuks Z, Kolesnick R |
Journal | Cell Physiol Biochem |
Volume | 56 |
Issue | 4 |
Pagination | 436-448 |
Date Published | 2022 Aug 31 |
ISSN | 1421-9778 |
Keywords | Animals, Ceramides, Colorectal Neoplasms, Disease Models, Animal, Humans, Neoplastic Stem Cells, Sphingomyelin Phosphodiesterase, Vascular System Injuries |
Abstract | 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 radiotherapy-induced 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. |
DOI | 10.33594/000000562 |
Alternate Journal | Cell Physiol Biochem |
PubMed ID | 36037065 |
Grant List | R01 CA158367 / CA / NCI NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States / / Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research / United States / / The Center Experimental Therapeutics at Memorial Sloan Kettering Cancer / United States / / Virginia and D.K. Ludwig Fund for Cancer Research / United States / / Larry and Stephanie Flinn Foundation / United States |