1. STING-dependent paracriny shapes apoptotic priming of breast tumors in response to anti-mitotic treatment.
- Author
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Lohard S, Bourgeois N, Maillet L, Gautier F, Fétiveau A, Lasla H, Nguyen F, Vuillier C, Dumont A, Moreau-Aubry A, Frapin M, David L, Loussouarn D, Kerdraon O, Campone M, Jézéquel P, Juin PP, and Barillé-Nion S
- Subjects
- Animals, Breast Neoplasms metabolism, Cell Line, Female, Gene Knockout Techniques, Humans, Interferon Type I genetics, Interferon Type I metabolism, Membrane Proteins genetics, Mice, Nucleotidyltransferases genetics, Nucleotidyltransferases metabolism, Paclitaxel pharmacology, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-2 metabolism, Signal Transduction drug effects, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha metabolism, Xenograft Model Antitumor Assays, bcl-X Protein antagonists & inhibitors, bcl-X Protein metabolism, Antimitotic Agents pharmacology, Apoptosis drug effects, Breast Neoplasms pathology, Membrane Proteins metabolism, Paracrine Communication drug effects
- 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.
- Published
- 2020
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