Anticancer chemotherapy and radiotherapy trigger both non-cell-autonomous and cell-autonomous death

Isabelle Martins (1, 2) , Syed Qasim Raza (1, 2, 3) , Laurent Voisin (1, 2) , Haithem Dakhli (1, 2) , Awatef Allouch (1, 2) , Frédéric Law (1, 2) , Dora Sabino (4) , Dorine de Jong (1, 2) , Maxime Thoreau (1, 2) , Elodie Mintet (1, 2) , Delphine Dugué (1, 2) , Mauro Piacentini (5, 6) , Marie-Lise Gougeon (7) , Fanny Jaulin (4) , Pascale Bertrand (8) , Catherine Brenner (9) , David M. Ojcius (10) , Guido Kroemer (11, 12, 13, 14) , Nazanine Modjtahedi (1, 2) , Eric Deutsch (1, 2) , Jean-Luc Perfettini (1, 2)

1 UMR 1030 - Radiothérapie moléculaire
2 Université Paris-Saclay
3 UVAS - University of Veterinary and Animal Sciences [Lahore, Pakistan]
4 U981 - Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse
5 National Institute for Infectious Diseases "Lazzaro Spallanzani"
6 Università degli Studi di Roma Tor Vergata [Roma] = University of Rome Tor Vergata
7 IABV - Immunité Anti-virale, Biothérapie et Vaccins
8 LREV - Laboratoire Réparation Et Vieillissement
9 Signalisation et physiopathologie cardiaque
10 University of the Pacific [San Francisco]
11 Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138 - Apoptose, cancer et immunité
12 Karolinska University Hospital [Stockholm]
13 Pôle de biologie
14 Plateforme de métabolomique

Even though cell death modalities elicited by anticancer chemotherapy and radiotherapy have been extensively studied, the ability of anticancer treatments to induce non-cell-autonomous death has never been investigated. By means of multispectral imaging flow-cytometry-based technology, we analyzed the lethal fate of cancer cells that were treated with conventional anticancer agents and co-cultured with untreated cells, observing that anticancer agents can simultaneously trigger cell-autonomous and non-cell-autonomous death in treated and untreated cells. After ionizing radiation, oxaliplatin, or cisplatin treatment, fractions of treated cancer cell populations were eliminated through cell-autonomous death mechanisms, while other fractions of the treated cancer cells engulfed and killed neighboring cells through non-cell-autonomous processes, including cellular cannibalism. Under conditions of treatment with paclitaxel, non-cell-autonomous and cell-autonomous death were both detected in the treated cell population, while untreated neighboring cells exhibited features of apoptotic demise. The transcriptional activity of p53 tumor-suppressor protein contributed to the execution of cell-autonomous death, yet failed to affect the non-cell-autonomous death by cannibalism for the majority of tested anticancer agents, indicating that the induction of non-cell-autonomous death can occur under conditions in which cell-autonomous death was impaired. Altogether, these results reveal that chemotherapy and radiotherapy can induce both non-cell-autonomous and cell-autonomous death of cancer cells, highlighting the heterogeneity of cell death responses to anticancer treatments and the unsuspected potential contribution of non-cell-autonomous death to the global effects of anticancer treatment.

Domaines: Cancer; Biologie cellulaire

Isabelle Martins, Syed Qasim Raza, Laurent Voisin, Haithem Dakhli, Awatef Allouch, et al.. Anticancer chemotherapy and radiotherapy trigger both non-cell-autonomous and cell-autonomous death. Cell Death and Disease, 2018, 9 (7), pp.716. ⟨10.1038/s41419-018-0747-y⟩. ⟨hal-02356534⟩