Compartmentalized Epidermal Activation of β-Catenin Differentially Affects Lineage Reprogramming and Underlies Tumor Heterogeneity.

Kai Kretzschmar,Ryan R Driskell,Christine Weber,Fiona M Watt,Eduardo Calonje

doi:10.1016/j.celrep.2015.12.041

Abstract

SummaryWnt/β-catenin activation in adult epidermis can induce new hair follicle formation and tumor development. We used lineage tracing to uncover the relative contribution of different stem cell populations. LGR6+ and LRIG1+ stem cells contributed to ectopic hair follicles formed in the sebaceous gland upon β-catenin activation, whereas LGR5+ cells did not. Lgr6, but not Lrig1 or Lgr5, was expressed in a subpopulation of interfollicular epidermal cells that were competent to form new hair follicles. Oncogenic β-catenin expression in LGR5+ cells led to formation of pilomatricomas, while LRIG1+ cells formed trichoadenomas and LGR6+ cells formed dermatofibromas. Tumor formation was always accompanied by a local increase in dermal fibroblast density and transient extracellular matrix remodeling. However, each tumor had a distinct stromal signature in terms of immune cell infiltrate and expression of CD26 and CD44. We conclude that compartmentalization of epidermal stem cells underlies different responses to β-catenin and skin tumor heterogeneity.

Highlights

Multiple epidermal stem cell subpopulations in adult mouse skin have been identified over the last decade (Kretzschmar and Watt, 2014; Solanas and Benitah, 2013)
The Wnt pathway plays a crucial role in epidermal development, homeostasis, and cancer (Blanpain et al, 2007; Lim and Nusse, 2013; Watt and Collins, 2008). b-Catenin activation is required for hair follicle (HF) morphogenesis during embryonic development and for the growth phase of the hair growth cycle in adult skin (Huelsken et al, 2001; Lim et al, 2013; Lowry et al, 2005; Niemann et al, 2002)
Lgr5-EGFP+ cells were found in the cycling portion of both telogen and anagen HFs (Figure 1B) (Jaks et al, 2008)

Summary

Introduction

Multiple epidermal stem cell subpopulations in adult mouse skin have been identified over the last decade (Kretzschmar and Watt, 2014; Solanas and Benitah, 2013). They tend to be competent to give rise to all the different epidermal lineages following transplantation, wounding, or genetic modification, under steady-state conditions, they maintain the epidermis in a compartmentalized manner (Page et al, 2013; Watt and Jensen, 2009). The different regions of the skin exhibit differential sensitivity to b-catenin, with SG being most sensitive and the HF bulge being highly insensitive (Baker et al, 2010; Deschene et al, 2014; Silva-Vargas et al, 2005)

Results

Discussion

Conclusion