Constitutive her2 signalling promotes breast cancer metastasis through cellular senescence

Resumo

INTRODUCTION: Various stresses, including active oncogenes and DNA-damage, are able to induce cells to a largely irreversible cell cycle arrest defined as premature cellular senescence. In the clinic, DNA-damaging cancer treatments induce either apoptosis or premature senescence, slowing down tumor progression. Despite the initial response, therapy-induced senescence might worsen the long-term clinical outcome. Indeed, upon treatment, senescent cancer cells are suggested to increase the rate of relapse through their Senescence Associated Secretory Phenotype (SASP). This work gives insight on how the activity of oncogenes expressed in senescent cancer cells modulates their SASP. RESULTS: The results presented in this dissertation show that p95HER2 is a truncated receptor able to signal as a HER2 homodimer stabilized by intermolecular disulphide-bonds. This constitutively active form of HER2 acts as a potent oncogene both in vitro and in vivo. It is shown that expression of this highly active HER2 fragment induces oncogenic senescence in different breast cancer cell lines. p95HER2-induced senescent cells actively produce a SASP enriched in protumorigenic factors. When senescent in response to a variety of non-oncogenic stimuli, including doxorubicin and ¿-irradiation, the same cells do not secrete the most of factors analyzed. At the same time, expression of the oncogene in proliferating breast epithelial cells has modest pro-secretory effects. However, evidence is provided that p95HER2 expression in irradiated senescent breast epithelial cells potently activates the secretion of various protumorigenic factors. These effects depend on p95HER2 activity as treatment with the tyrosine kinase inhibitor Lapatinib dramatically impairs the secretory response in all cases studied. Preliminary evidence implicates NFkB transcriptional activity and the PI3K-AKT-mTOR pathway as mediators of the p95HER2-dependent protumorigenic SASP. Finally, using in vivo imaging, these results suggest that p95HER2-expressing senescent cells exert a cell-non-autonomous prometastatic effect. This effect, likely due to the SASP, is observed both at the local and at the systemic level. CONCLUSIONS: Constitutive HER2 signalling potentiates and controls the secretory response of senescent breast epithelial cells. In vivo, the presence of senescent cells expressing p95HER2, within a primary tumor, correlates with increased metastatic capacity of non-senescent luciferase-expressing tumor cells (either present in the same tumor or circulating). We speculate that senescent cancer cells in which certain signalling pathways are over-activated might exert similar protumorigenic effects. This makes relevant to further explore the impact of oncogenes expression on the secretome of senescent cancer cells. These findings also suggest that, whenever possible, appropriate inhibitors able to dampen the SASP should be administered together with senescence-inducing cancer treatments. Senescent cancer cells-targeted therapy could also represent an interesting new opportunity. In the eventuality of cancer therapy-induced senescence, such interventions would restrain the detrimental effects of the SASP, hopefully improving the long-term clinical outcome of some patients.