S Bodo, C Campagne, TH Thin, DS Higginson, HA Vargas, G Hua, JD Fuller, E Ackerstaff, J Russell, Z Zhang, S Klingler, H Cho, MG Kaag, Y Mazaheri, A Rimner, K Manova-Todorova, B Epel, J Zatcky, CR Cleary, SS Rao, Y Yamada, MJ Zelefsky, HJ Halpern, JA Koutcher, C Cordon-Cardo, C Greco, A Haimovitz-Friedman, E Sala, SN Powell, R Kolesnick, Z Fuks
Journal name: 
J Clin Invest
Citation info: 
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.
E-pub date: 
31 Jan 2019
Users with this publication listed: 
Evis Sala