Skin is an excellent tool to study tissue homeostasis and the onset of cancer formation since the epidermis of the skin is one of the best-studied stem cell (SC) systems and cancer is believed to arise from deregulated stem and progenitor cell populations. Epidermal SCs are located in distinct SC niches of the hair follicle (HF), the sebaceous gland and the interfollicular epidermis (IFE) and their respective progeny are restricted to defined areas. However, injuries like acute wounds disturb the balance of homeostasis and allow SC progeny to repopulate new areas. Cancer also disturbs – or needs a disturbed – homeostasis, suggesting that the microenvironment, or certain niches, play a critical role in cancer initiation.
In order to build a comprehensive picture of skin homeostasis and cancer initiation we will:
A. Delineate the contribution pattern of individual epidermal SCs during homeostasis, and investigate the ability of a wound to reprogram SCs.
B. Create a complete skin map during development and homeostasis using single-cell RNA-sequencing.
C. Investigate the roles of distinct SC niches in tumor formation.
D. Uncover the molecular regulation of SCs, regenerative wound-front cells, newly transformed cancer-initiating cells and their respective niches.
The proposed research will for the first time generate a complete cell map of a functional mammalian organ at single cell resolution, unravel the level of SC diversity and plasticity, and reveal how SC niches and wound healing influence skin cancer development. The results will lead to a major advance in our understanding of basic mechanisms of tissue maintenance and cancer initiation with potential for generalization to other tissues and many types of cancer.