Skip to Main content Skip to Navigation
Journal articles

STING-dependent paracriny shapes apoptotic priming of breast tumors in response to anti-mitotic treatment

Abstract : A fascinating but uncharacterized action of antimitotic chemotherapy is to collectively prime cancer cells to apoptotic mitochondrial outer membrane permeabilization (MOMP), while impacting only on cycling cell subsets. Here, we show that a proapoptotic secretory phenotype is induced by activation of cGAS/STING in cancer cells that are hit by antimitotic treatment, accumulate micronuclei and maintain mitochondrial integrity despite intrinsic apoptotic pressure. Organotypic cultures of primary human breast tumors and patient-derived xenografts sensitive to paclitaxel exhibit gene expression signatures typical of type I IFN and TNFα exposure. These cytokines induced by cGAS/STING activation trigger NOXA expression in neighboring cells and render them acutely sensitive to BCL-xL inhibition. cGAS/STING-dependent apoptotic effects are required for paclitaxel response in vivo, and they are amplified by sequential, but not synchronous, administration of BH3 mimetics. Thus anti-mitotic agents propagate apoptotic priming across heterogeneously sensitive cancer cells through cytosolic DNA sensing pathway-dependent extracellular signals, exploitable by delayed MOMP targeting.
Complete list of metadatas

Cited literature [67 references]  Display  Hide  Download

https://www.hal.inserm.fr/inserm-02448103
Contributor : Elizabeth Bernardo <>
Submitted on : Wednesday, January 22, 2020 - 9:24:00 AM
Last modification on : Tuesday, March 17, 2020 - 3:42:25 AM

File

Lohard2020eQ8.pdf
Publication funded by an institution

Identifiers

Citation

Steven Lohard, Nathalie Bourgeois, Laurent Maillet, Fabien Gautier, Aurélie Fétiveau, et al.. STING-dependent paracriny shapes apoptotic priming of breast tumors in response to anti-mitotic treatment. Nature Communications, Nature Publishing Group, 2020, 11 (1), pp.259. ⟨10.1038/s41467-019-13689-y⟩. ⟨inserm-02448103⟩

Share

Metrics

Record views

140

Files downloads

116