The ICE team is working on molecular mechanisms involved in the initiation of epithelial cell transformation. The efforts are focused on the mechanisms enabling escape from senescence that could favour the initial emergence of transformed cells.

Carcinomas -the cancers originating from epithelial cells- are the most frequent human cancers. Their incidence is almost zero in people under 20 and reaches a peak in the 45-74 years-old group. Cancers originating from other cell types are much rarer and most of them, notably sarcomas, brain tumors and some leukemia such as acute lymphocytic leukemia, occur preferentially in young people or at the same frequency whatever the group of age (NCI statistics). Therefore, aging seems to have a powerful tumorigenic potential restricted to carcinomas. In the Initiation of Epithelial Cancer (ICE) team, we are working since 2002 on how the molecular mechanisms of cellular aging impact on malignant transformation. As a model, we have chosen non-melanoma skin carcinoma (NMSC) which is the most frequent carcinoma of aged populations. Skin is made of a pluristratified epithelium, the epidermis, containing mainly keratinocytes, an underlying dermis containing mainly fibroblasts, and a hypodermis containing adipocytes. The two major NMSCs, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), derive from transit amplifying epidermal keratinocytes of the basal layer for BCC, or from more differentiated keratinocytes of the upper layer and stem cells of the hairy follicle bulge for SSC. In contrast to NMSCs, soft-tissue sarcomas including those arising from skin are very uncommon, about only 1% of all cancers. Our general aim is to decipher the molecular pathways that could explain why these two tissues have a so different propensity to undergo malignant transformation during aging. One of our hypotheses is that the intrinsic mechanisms of keratinocyte and fibroblast senescence could differ and make these two cell types differently prone to transform. For that purpose, we use a model we have established of in vitro cultured normal human epidermal keratinocytes (NHEKs) that recapitulate ageing and the early events of cellular transformation.

1- We explore the role of oxidatively-induced DNA damage in both senescence and post-senescence neoplastic emergence of these cells.

2- We also investigate the involvement of endoplasmic reticulum stress and autophagic activity in the outcome of senescent NHEKs, i.e. cell death or neoplastic escape.

3- The other mechanism we also investigate is an alteration with aging of the paracrine interactions between epidermis and dermis which could differently direct the outcome of each cell type.

4- Recently, we became interested in the model of second cancers developing after radiotherapy, with the hypothesis that radiations could recapitulate some events occurring with normal aging.

Fig_MMP

MMP gelatinolytic activity on histological sections of skin from healthy human donors. Ep:epidermis; Dp:papillary dermis; Dr:reticular dermis; dot-line: basal lamina. Bar 25mm