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

Sahra Bodo, Cécile Campagne, Tin Htwe Thin, Daniel S. Higginson, H. Alberto Vargas, Guoqiang Hua, John D. Fuller, Ellen Ackerstaff, James Russell, Zhigang Zhang, Stefan Klingler, Hyung Joon Cho, Matthew G. Kaag, Yousef Mazaheri, Andreas Rimner, Katia Manova-Todorova, Boris Epel, Joan Zatcky, Cristian R. Cleary, Shyam RaoYoshiya Yamada, Michael J. Zelefsky, Howard J. Halpern, Jason A. Koutcher, Carlos Cordon-Cardo, Carlo Greco, Adriana Haimovitz-Friedman, Evis Sala, Simon N. Powell, Richard Kolesnick, Zvi Fuks

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)786-801
Number of pages16
JournalJournal of Clinical Investigation
Volume129
Issue number2
DOIs
StatePublished - Feb 1 2019
Externally publishedYes

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Homologous Recombination
Reperfusion Injury
Radiotherapy
Neoplasms
Vasoconstriction
Chromatin
Peroxiredoxin VI
Double-Stranded DNA Breaks
Endothelin-1
Chromosome Aberrations
Reperfusion
Ischemia
Randomized Controlled Trials
Perfusion

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bodo, S., Campagne, C., Thin, T. H., Higginson, D. S., Vargas, H. A., Hua, G., ... Fuks, Z. (2019). Single-dose radiotherapy disables tumor cell homologous recombination via ischemia/reperfusion injury. Journal of Clinical Investigation, 129(2), 786-801. https://doi.org/10.1172/JCI97631

Single-dose radiotherapy disables tumor cell homologous recombination via ischemia/reperfusion injury. / Bodo, Sahra; Campagne, Cécile; Thin, Tin Htwe; Higginson, Daniel S.; Vargas, H. Alberto; Hua, Guoqiang; Fuller, John D.; Ackerstaff, Ellen; Russell, James; Zhang, Zhigang; Klingler, Stefan; Cho, Hyung Joon; Kaag, Matthew G.; Mazaheri, Yousef; Rimner, Andreas; Manova-Todorova, Katia; Epel, Boris; Zatcky, Joan; Cleary, Cristian R.; Rao, Shyam; Yamada, Yoshiya; Zelefsky, Michael J.; Halpern, Howard J.; Koutcher, Jason A.; Cordon-Cardo, Carlos; Greco, Carlo; Haimovitz-Friedman, Adriana; Sala, Evis; Powell, Simon N.; Kolesnick, Richard; Fuks, Zvi.

In: Journal of Clinical Investigation, Vol. 129, No. 2, 01.02.2019, p. 786-801.

Research output: Contribution to journalArticle

Bodo, S, Campagne, C, Thin, TH, Higginson, DS, Vargas, HA, Hua, G, Fuller, JD, Ackerstaff, E, Russell, J, Zhang, Z, Klingler, S, Cho, HJ, Kaag, MG, Mazaheri, Y, Rimner, A, Manova-Todorova, K, Epel, B, Zatcky, J, Cleary, CR, Rao, S, Yamada, Y, Zelefsky, MJ, Halpern, HJ, Koutcher, JA, Cordon-Cardo, C, Greco, C, Haimovitz-Friedman, A, Sala, E, Powell, SN, Kolesnick, R & Fuks, Z 2019, 'Single-dose radiotherapy disables tumor cell homologous recombination via ischemia/reperfusion injury', Journal of Clinical Investigation, vol. 129, no. 2, pp. 786-801. https://doi.org/10.1172/JCI97631
Bodo, Sahra ; Campagne, Cécile ; Thin, Tin Htwe ; Higginson, Daniel S. ; Vargas, H. Alberto ; Hua, Guoqiang ; Fuller, John D. ; Ackerstaff, Ellen ; Russell, James ; Zhang, Zhigang ; Klingler, Stefan ; Cho, Hyung Joon ; Kaag, Matthew G. ; Mazaheri, Yousef ; Rimner, Andreas ; Manova-Todorova, Katia ; Epel, Boris ; Zatcky, Joan ; Cleary, Cristian R. ; Rao, Shyam ; Yamada, Yoshiya ; Zelefsky, Michael J. ; Halpern, Howard J. ; Koutcher, Jason A. ; Cordon-Cardo, Carlos ; Greco, Carlo ; Haimovitz-Friedman, Adriana ; Sala, Evis ; Powell, Simon N. ; Kolesnick, Richard ; Fuks, Zvi. / Single-dose radiotherapy disables tumor cell homologous recombination via ischemia/reperfusion injury. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 2. pp. 786-801.
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AU - Bodo, Sahra

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AU - Higginson, Daniel S.

AU - Vargas, H. Alberto

AU - Hua, Guoqiang

AU - Fuller, John D.

AU - Ackerstaff, Ellen

AU - Russell, James

AU - Zhang, Zhigang

AU - Klingler, Stefan

AU - Cho, Hyung Joon

AU - Kaag, Matthew G.

AU - Mazaheri, Yousef

AU - Rimner, Andreas

AU - Manova-Todorova, Katia

AU - Epel, Boris

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AU - Cleary, Cristian R.

AU - Rao, Shyam

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AU - Zelefsky, Michael J.

AU - Halpern, Howard J.

AU - Koutcher, Jason A.

AU - Cordon-Cardo, Carlos

AU - Greco, Carlo

AU - Haimovitz-Friedman, Adriana

AU - Sala, Evis

AU - Powell, Simon N.

AU - Kolesnick, Richard

AU - Fuks, Zvi

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