Abstract SY10-01: Uncovering the cellular origin of skin cancers

Abstract

Abstract Stem cells (SCs) are responsible for tissue homeostasis and repair. SCs have been hypothesized to be the cells at the origin of cancer. However, for the vast majority of cancers, the cell at the origin of tumor initiation is still unknown. Two epithelial skin cancers are frequent in human populations: the basal cell carcinoma (BCC) and the squamous cell carcinoma (SCC). We developed new genetic approaches to identify the cells at the origin of BCC and SCC in mice. Using mice conditionally expressing constitutively active Smoothened mutant (SmoM2) or KRas mutant (G12D), we activated hedgehog or Ras signaling in different cellular compartments of the skin epidermis, and determined from which epidermal compartments oncogene expression induces cancer formation. Using clonal analysis, we found that SmoM2 induced BCC arise from long-term resident progenitor cells of the interfollicular epidermis. In contrast, expression of mutant KRas in hair follicle bulge stem cells (SCs), but not in their transient amplifying progeny, led to benign squamous skin tumor (papilloma). Whereas no malignant tumor was observed following KRasG12D expression alone, expression of KRasG12D combined with the loss of p53 induced invasive SCC formation (3). Our studies uncover the cells at the origin of SmoM2 induced BCC and and Kras induced SCC in mice and demonstrate that expression of differentiation markers in tumor cells is not necessary predictive of the cancer initiating cells. We have now developed novel strategy to isolate by flow cytometry oncogene targeted cells at different time following oncogene expression and determined the molecular changes associated with tumor initiation and malignant progression. The functional relevance of these genes is currently investigated using gain and loss of function in mice. These new results and the relevance of these findings to human skin cancers will be presented. Acknowledgement This work is supported by Welbio, the FNRS, the program d'excellence CIBLES of the Wallonia Region, Fondation Contre le Cancer, the European Research Council (ERC) and the EMBO Young Investigator Program. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY10-01. doi:1538-7445.AM2012-SY10-01