Breast cancer stem cell-like cells generated during TGFβ-induced EMT are radioresistant

// Julie Konge 1 , Francois Leteurtre 1 , Maud Goislard 1 , Denis Biard 2 , Sandrine Morel-Altmeyer 1 , Aurelie Vaurijoux 3 , Gaetan Gruel 3 , Sylvie Chevillard 1, * and Jerome Lebeau 1, * 1 CEA, Institut de Biologie Francois Jacob, DSV, iRCM, SREIT, Laboratoire de Cancerologie Experimentale (LCE), Universite Paris-Saclay, F-92265 Fontenay-aux-Roses, France 2 CEA, Institut de Biologie Francois Jacob, SEPIA, Team Cellular Engineering and Human Syndromes, Universite Paris-Saclay, F-92265 Fontenay-aux-Roses, France 3 Institut de Radioprotection et de Surete Nucleaire (IRSN), Laboratoire de Dosimetrie Biologique, 92262 Fontenay-aux-Roses Cedex, France * These authors contributed equally to this work Correspondence to: Jerome Lebeau, email: jerome.lebeau@cea.fr Keywords: epithelial-mesenchymal transition; breast cancer; radioresistance; cancer stem cells Received: August 24, 2017      Accepted: April 04, 2018      Published: May 04, 2018 ABSTRACT Failure of conventional antitumor therapy is commonly associated with cancer stem cells (CSCs), which are often defined as inherently resistant to radiation and chemotherapeutic agents. However, controversy about the mechanisms involved in the radiation response remains and the inherent intrinsic radioresistance of CSCs has also been questioned. These discrepancies observed in the literature are strongly associated with the cell models used. In order to clarify these contradictory observations, we studied the radiosensitivity of breast CSCs using purified CD24 −/low /CD44 + CSCs and their corresponding CD24 + /CD44 low non-stem cells. These cells were generated after induction of the epithelial-mesenchymal transition (EMT) by transforming growth factor β (TGFβ) in immortalized human mammary epithelial cells (HMLE). Consequently, these 2 cellular subpopulations have an identical genetic background, their differences being related exclusively to TGFβ-induced cell reprogramming. We showed that mesenchymal CD24 −/low /CD44 + CSCs are more resistant to radiation compared with CD24 + /CD44 low parental cells. Cell cycle distribution and free radical scavengers, but not DNA repair efficiency, appeared to be intrinsic determinants of cellular radiosensitivity. Finally, for the first time, we showed that reduced radiation-induced activation of the death receptor pathways (FasL, TRAIL and TNF-α) at the transcriptional level was a key causal event in the radioresistance of CD24 −/low / CD44+ cells acquired during EMT.