Laboratory of Signal Transduction Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, USA.
Cell Physiol Biochem. 2022 Aug 31;56(4):436-448. doi: 10.33594/000000562.
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.
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.
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.
We posit homologous recombination repair represents a vulnerability determining colorectal cancer stem cell fate, approachable therapeutically using single dose radiotherapy.
背景/目的：目前尚不清楚癌症干细胞与后代相比是否对治疗有不同的反应，这可能提供了治疗上的弱点。我们的计划开创了使用超高单次剂量放疗的先河，这种疗法比常规分割（~65%）更高的治愈率（90-95%）治愈了多种转移性疾病。单次剂量放疗涉及一种独特的生物学机制，涉及微血管酸性鞘磷脂酶/神经酰胺信号，通过 NADPH 氧化酶-2 依赖性灌注缺陷，引发适应性肿瘤 SUMO 应激反应，使同源重组修复双链断裂的能力全面失活，从而实现治愈。越来越多的数据表明，不同的干细胞对同源重组修复的依赖性更高，以修复双链断裂。
在这里，我们使用含有对数增加的 Lgr5+干细胞的结直肠癌患者来源异种移植物来探索是否优化这种酸性鞘磷脂酶依赖性生物学的参与是否可以增强干细胞依赖性肿瘤的治愈。
我们发现耐辐射的结直肠癌患者来源异种移植物 CLR27-2 含有耐辐射的微血管和干细胞，而辐射敏感的结直肠癌患者来源异种移植物 CLR1-1 含有辐射敏感的微血管和干细胞。药物或基因治疗增强单次剂量放疗诱导的酸性鞘磷脂酶/神经酰胺介导的微血管功能障碍，可显著增强 CLR27-2 的同源重组修复失活，将 Lgr5+细胞从最耐药的患者来源异种移植物群体转变为最敏感的群体，从而实现肿瘤治愈。
我们认为同源重组修复是决定结直肠癌干细胞命运的一个弱点，可以通过单次剂量放疗进行治疗。
