RésuméCellular senescence is defined as an irreversible growth arrest to avoid the proliferation of damaged cells. It gathers replicative senescence, associated with the critical telomere shortening, but also stress-induced premature senescence (SIPS), generated by DNA damage and/or oxidative stress. Interestingly, senescent cells remain metabolically active and secrete growth factors, cytokines, chemokines and proteases, which are referred as the senescence-associated secretory phenotype (SASP). They are therefore able to communicate with their microenvironment and are associated with numerous beneficial and detrimental roles. Their involvement in carcinogenesis has been highlighted in several cancer types via the promotion of tumour cell growth, migration and invasion.
Cutaneous Squamous Cell Carcinoma (cSCC) is the second most common skin cancer in white-skinned populations. Its occurrence is associated with ageing and lifelong cumulative sunlight exposure, which are both characterised by the accumulation of senescent cells. However, the link between these two processes is poorly understood.
In this thesis, we compared two relevant in vitro models of senescence in the context of skin ageing and cSCC, namely replicative senescence and UVB-SIPS, in dermal human diploid fibroblasts (HDFs). We studied their interaction with three cSCC cell lines representing different stages of squamous epidermal carcinogenesis. These stages are carcinoma in situ, invasive primary SCC and distant lymph node metastasis. Finally, we also investigated the signalling pathways activated in dermal HDFs in UVB-SIPS.
We found that replicative senescence and UVB-SIPS HDFs display a common but also a specific expression of SASP-related genes. Moreover, our results demonstrate cellular interactions within the cSCC microenvironment. We first showed a limited impact of conditioned media collected from senescent fibroblasts and indirect co- cultures on cSCC cell growth and migration. Then, we investigated the opposite interaction and found that cSCC cells maintained in indirect co-cultures with fibroblasts induced and reinforced their senescence state. Furthermore, these effects were modulated according to the stage of tumourigenesis of the different cSCC cell lines used. Finally, regarding the signalling pathway activated in UVB-SIPS, we did not show any sign of activation of the canonical Smad pathway but we did detect a persistent activation of the DNA damage response pathway.
Overall, understanding the interplay between cancer cells and their microenvironment may have important outcomes in cancer research and therapeutic strategies. The question that remains open is whether these results might explain the accumulation of senescent cells at site of neoplasia.
|la date de réponse||9 nov. 2018|
|Superviseur||Florence Chainiaux Debacq (Promoteur), Carine MICHIELS (Président), Yves Poumay (Jury), Patrick Dumont (Jury) & Isabelle Petropoulos (Jury)|