Candice Merle1,2, Pauline Lagarde3, Lydia Lartigue3,4, Frédéric Chibon5,6,7. 1. INSERM U1037, Cancer Research Center in Toulouse (CRCT), 31037, Toulouse, France. 2. University of Toulouse 3, Paul Sabatier, 118 route de Narbonne, 31062, Toulouse Cedex 9, France. 3. INSERM U1218, 229 cours de l'Argonne, F-33076, Bordeaux, France. 4. University of Bordeaux, 146 rue Léo Saignat, F-33000, Bordeaux, France. 5. INSERM U1037, Cancer Research Center in Toulouse (CRCT), 31037, Toulouse, France. frederic.chibon@inserm.fr. 6. Institut Claudius Régaud, IUCT-Oncopole, Toulouse, France. frederic.chibon@inserm.fr. 7. Present address: CRCT-IUCT-O, 2 avenue Hubert Curien, 31037, Toulouse Cedex 1, France. frederic.chibon@inserm.fr.
Abstract
BACKGROUND: Cancer stem/Initiating cell (CS/IC) hypothesis argues that CS/ICs are responsible of tumour initiation, drug resistance, metastasis or disease relapse. Their detection in several cancers supports this concept. However, their origin is still misunderstood. Cell fusion is shown to take part in the formation of CS/ICs, i.e. fusion between mesenchymal stem cell and cancer cell. In a previous paper, we described that fusion leads to hybrids with metastatic capacity. This process triggered genomic rearrangements in hybrid cells together with increased metastasis development. Here, we hypothesize that cell fusion could be strong enough to provoke a cellular reprogramming and the acquisition of CS/IC properties, promoting metastasis formation. METHODS: After spontaneous cell fusion between E6E7 (IMR90 with the oncogenes E6 and E7) and RST (IMR90 fully transformed) cell lines, hybrid cells were selected by dual antibiotic selection. Cancer stem cells capacities were evaluated regarding capacity to form spheres, expression of stem cell markers and the presence of ALDHhigh cells. RESULTS: Our data show that after cell fusion, all hybrids contain a percentage of cells with CS/ICs properties, regarding. Importantly, we lastly showed that NANOG inhibition in H1 hybrid decreases this migration capacity while having no effect on the corresponding parental cells. CONCLUSIONS: Altogether these results indicate that the combination of CS/ICs properties and genomic rearrangement in hybrids is likely to be key to tumour progression.
BACKGROUND:Cancer stem/Initiating cell (CS/IC) hypothesis argues that CS/ICs are responsible of tumour initiation, drug resistance, metastasis or disease relapse. Their detection in several cancers supports this concept. However, their origin is still misunderstood. Cell fusion is shown to take part in the formation of CS/ICs, i.e. fusion between mesenchymal stem cell and cancer cell. In a previous paper, we described that fusion leads to hybrids with metastatic capacity. This process triggered genomic rearrangements in hybrid cells together with increased metastasis development. Here, we hypothesize that cell fusion could be strong enough to provoke a cellular reprogramming and the acquisition of CS/IC properties, promoting metastasis formation. METHODS: After spontaneous cell fusion between E6E7 (IMR90 with the oncogenes E6 and E7) and RST (IMR90 fully transformed) cell lines, hybrid cells were selected by dual antibiotic selection. Cancer stem cells capacities were evaluated regarding capacity to form spheres, expression of stem cell markers and the presence of ALDHhigh cells. RESULTS: Our data show that after cell fusion, all hybrids contain a percentage of cells with CS/ICs properties, regarding. Importantly, we lastly showed that NANOG inhibition in H1 hybrid decreases this migration capacity while having no effect on the corresponding parental cells. CONCLUSIONS: Altogether these results indicate that the combination of CS/ICs properties and genomic rearrangement in hybrids is likely to be key to tumour progression.
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