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Single-dose radiotherapy disables tumor cell homologous recombination via ischemia/reperfusion injury.

ABSTRACT: Tumor cure with conventional fractionated radiotherapy is 65%, dependent on tumor cell-autonomous gradual buildup of DNA double-strand break (DSB) misrepair. Here we report that single-dose radiotherapy (SDRT), a disruptive technique that ablates more than 90% of human cancers, operates a distinct dual-target mechanism, linking acid sphingomyelinase-mediated (ASMase-mediated) microvascular perfusion defects to DNA unrepair in tumor cells to confer tumor cell lethality. ASMase-mediated microcirculatory vasoconstriction after SDRT conferred an ischemic stress response within parenchymal tumor cells, with ROS triggering the evolutionarily conserved SUMO stress response, specifically depleting chromatin-associated free SUMO3. Whereas SUMO3, but not SUMO2, was indispensable for homology-directed repair (HDR) of DSBs, HDR loss of function after SDRT yielded DSB unrepair, chromosomal aberrations, and tumor clonogen demise. Vasoconstriction blockade with the endothelin-1 inhibitor BQ-123, or ROS scavenging after SDRT using peroxiredoxin-6 overexpression or the SOD mimetic tempol, prevented chromatin SUMO3 depletion, HDR loss of function, and SDRT tumor ablation. We also provide evidence of mouse-to-human translation of this biology in a randomized clinical trial, showing that 24 Gy SDRT, but not 3×9 Gy fractionation, coupled early tumor ischemia/reperfusion to human cancer ablation. The SDRT biology provides opportunities for mechanism-based selective tumor radiosensitization via accessing of SDRT/ASMase signaling, as current studies indicate that this pathway is tractable to pharmacologic intervention.

SUBMITTER: Bodo S

PROVIDER: S-EPMC6355243 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Single-dose radiotherapy disables tumor cell homologous recombination via ischemia/reperfusion injury.

Bodo Sahra S Campagne Cécile C Thin Tin Htwe TH Higginson Daniel S DS Vargas H Alberto HA Hua Guoqiang G Fuller John D JD Ackerstaff Ellen E Russell James J Zhang Zhigang Z Klingler Stefan S Cho HyungJoon H Kaag Matthew G MG Mazaheri Yousef Y Rimner Andreas A Manova-Todorova Katia K Epel Boris B Zatcky Joan J Cleary Cristian R CR Rao Shyam S SS Yamada Yoshiya Y Zelefsky Michael J MJ Halpern Howard J HJ Koutcher Jason A JA Cordon-Cardo Carlos C Greco Carlo C Haimovitz-Friedman Adriana A Sala Evis E Powell Simon N SN Kolesnick Richard R Fuks Zvi Z

The Journal of clinical investigation 20190114 2

Tumor cure with conventional fractionated radiotherapy is 65%, dependent on tumor cell-autonomous gradual buildup of DNA double-strand break (DSB) misrepair. Here we report that single-dose radiotherapy (SDRT), a disruptive technique that ablates more than 90% of human cancers, operates a distinct dual-target mechanism, linking acid sphingomyelinase-mediated (ASMase-mediated) microvascular perfusion defects to DNA unrepair in tumor cells to confer tumor cell lethality. ASMase-mediated microcircu ...[more]

PMID: 30480549

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Project description:Timely reperfusion after a myocardial infarction is necessary to salvage the ischemic region; however, reperfusion itself is also a major contributor to the final tissue damage. Currently, there is no clinically relevant therapy available to reduce ischemia-reperfusion injury (IRI). While many drugs have shown promise in reducing IRI in preclinical studies, none of these drugs have demonstrated benefit in large clinical trials. Part of this failure to translate therapies can be attributed to the reliance on small animal models for preclinical studies. While animal models encapsulate the complexity of the systemic in vivo environment, they do not fully recapitulate human cardiac physiology. Furthermore, it is difficult to uncouple the various interacting pathways in vivo. In contrast, in vitro models using isolated cardiomyocytes allow studies of the direct effect of therapeutics on cardiomyocytes. External factors can be controlled in simulated ischemia-reperfusion to allow for better understanding of the mechanisms that drive IRI. In addition, the availability of cardiomyocytes derived from human induced pluripotent stem cells (hIPS-CMs) offers the opportunity to recapitulate human physiology in vitro. Unfortunately, hIPS-CMs are relatively fetal in phenotype, and are more resistant to hypoxia than the mature cells. Tissue engineering platforms can promote cardiomyocyte maturation for a more predictive physiologic response. These platforms can further be improved upon to account for the heterogenous patient populations seen in the clinical settings and facilitate the translation of therapies. Thereby, the current preclinical studies can be further developed using currently available tools to achieve better predictive drug testing and understanding of IRI. In this article, we discuss the state of the art of in vitro modeling of IRI, propose the roles for tissue engineering in studying IRI and testing the new therapeutic modalities, and how the human tissue models can facilitate translation into the clinic.

Dataset Information

Single-dose radiotherapy disables tumor cell homologous recombination via ischemia/reperfusion injury.

Publications

Single-dose radiotherapy disables tumor cell homologous recombination via ischemia/reperfusion injury.

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