Cell competition was originally described in Drosophila as a physiological process based on the comparison of relative fitness between neighbouring cells. At the end of the process, suboptimal cells, called losers, are committed to die while stimulating proliferation of the most performant cells, called winners, so maintaining tissue homeostasis. In Drosophila and mammalian development, cells showing high MYC activity behave like winners, growing at the expense of the surrounding cells which succumb by apoptosis, so unveiling a leading role for this oncoprotein in eliciting cell competition. Since MYC protein is upregulated in a large fraction of human cancers, cell competition has been speculated to play a role in human tumourigenesis. Consistently with this hypothesis, we found massive apoptotic death of stromal cells in proximity to MYC-upregulating cancer cells in a relevant number of human tumour samples, and showed that modulation of MYC activity in human cancer cell lines is sufficient to subvert their competitive drive. In Drosophila, MYC-overexpressing cells have been demonstrated to be unable to execute cell competition in a p53 loss-of-function background. With the aim to find a role for p53 in MYC-mediated cell competition, we first stained the same cancer samples as above for p53. Interestingly, the tumour regions that did not show significant signs of competitive interactions were also found negative for p53 staining, disclosing a possible function for this protein in promoting cancer-associated cell competition. Further experiments in a¬ Drosophila cancer model helped us define a dose-dependent role of p53 in MYC-overexpressing winner cells, and functional assays in co-cultures of human cancer cells confirmed that p53 function is necessary for the winner cells to execute cell competition. Altogether, our findings reveal a pro-oncogenic role of p53, that appears to cooperate with MYC in driving cell competition in different cancer contexts.
Di Giacomo, S., Sollazzo, M., Paglia, S., Dario de Biase, ., Pession, A., Grifoni, D. (2017). p53 Modulates MYC-Mediated Cell Competition in Different Cancer Contexts.
p53 Modulates MYC-Mediated Cell Competition in Different Cancer Contexts
DI GIACOMO, SIMONE;SOLLAZZO, MANUELA;PAGLIA, SIMONA;DE BIASE, DARIO;PESSION, ANNALISA;GRIFONI, DANIELA
2017
Abstract
Cell competition was originally described in Drosophila as a physiological process based on the comparison of relative fitness between neighbouring cells. At the end of the process, suboptimal cells, called losers, are committed to die while stimulating proliferation of the most performant cells, called winners, so maintaining tissue homeostasis. In Drosophila and mammalian development, cells showing high MYC activity behave like winners, growing at the expense of the surrounding cells which succumb by apoptosis, so unveiling a leading role for this oncoprotein in eliciting cell competition. Since MYC protein is upregulated in a large fraction of human cancers, cell competition has been speculated to play a role in human tumourigenesis. Consistently with this hypothesis, we found massive apoptotic death of stromal cells in proximity to MYC-upregulating cancer cells in a relevant number of human tumour samples, and showed that modulation of MYC activity in human cancer cell lines is sufficient to subvert their competitive drive. In Drosophila, MYC-overexpressing cells have been demonstrated to be unable to execute cell competition in a p53 loss-of-function background. With the aim to find a role for p53 in MYC-mediated cell competition, we first stained the same cancer samples as above for p53. Interestingly, the tumour regions that did not show significant signs of competitive interactions were also found negative for p53 staining, disclosing a possible function for this protein in promoting cancer-associated cell competition. Further experiments in a¬ Drosophila cancer model helped us define a dose-dependent role of p53 in MYC-overexpressing winner cells, and functional assays in co-cultures of human cancer cells confirmed that p53 function is necessary for the winner cells to execute cell competition. Altogether, our findings reveal a pro-oncogenic role of p53, that appears to cooperate with MYC in driving cell competition in different cancer contexts.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
