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Titre de la communication :
CXCL1 and CCL5, induced by ionizing radiation, reprogram non-tumorigenic cancer cells into resistant cancer stem cells in breast cancer.
Auteurs (et leurs adresses) de la communication :
Bailleul J1, Bidan N1, Mouttet-Audouard R2, Arcicasa M1,2, Hannebicque K2, Takayama Y1,3, Meignan S1,2, Le Bourhis X1, Lagadec C1 1,INSERM U908, Lille 1, France. 2,Centre Oscar Lambret, France. 3, LIMMS/CNRS-IIS UMI2080, SMMIL-E, Japan.
Résumé de la communication :
Identification of cancer stem cells (CSC) in solid tumours – with self-renewal, multipotency, tumorigenesis, and therapy resistance capacities – has opened path to new targeting therapeutic approaches. However, CSC targeting alone might not be sufficient to eradicate a tumour. Indeed, recent studies showed that cancer cells are plastic, and conventional therapies, such as radiotherapy, can lead to cancer cells (non-CSC) reprogramming into iCSC (induced-CSC). The goal of our work is to identify the molecular mechanisms responsible for treatment-induced CSC emergence.

First, we have shown that conditioned media from irradiated non-CSC is sufficient to induce iCSC reprogramming. These results suggest that cell plasticity might be actively regulated by diffusible factors secreted by irradiated cells. By using proteins arrays and ELISA, we demonstrated that the secretion of a specific cocktail of chemokines is induced by ionizing radiation, such as CXCL1 and CCL5. Interestingly, recombinant CXCL1 and CCL5 treatments increase the sphere forming capacity (SFC) of isolated non-CSC treated population. Concomitantly, treatment with neutralizing antibodies targeting CXCL1 and CCL5 leads to a decreased CSC number (ALDH+ cells).
We also studied the expression of the corresponding chemokines receptors, by flow cytometry. First, we saw that reprogrammable ALDH- cells are enriched for CXCL1 and CCL5 receptors expressing cells compare to unsorted population or ALDH+ population (CSC). We analysed the reprogramming potential of isolated ALDH-/receptor-positive cells versus ALDH-/receptor-negative cells. Unfortunately, our results were inconclusive. However, we then looked at ionizing radiation effect on receptors expression in a sorted non-CSC receptor negative population. Interestingly, we found that the expressing receptors cell population was back to basal level, within five days, in an irradiation-independent manner.

To validate the implication of CXCL1 and CCL5 in the reprogramming mechanism and in a pre-clinical perspective, we are currently evaluating the effect on reprogramming of siRNA targeting CXCL1 and CCL5, and pharmacological inhibitors of their receptors. The exciting first results show a decreased reprogramming capacity of the treated cells.