Basal cell carcinomas in mice arise from hair follicle stem cells and multiple epithelial progenitor populations

Grachtchouk, Marina; Pero, Joanna; Yang, Steven; Ermilov, A. Yu.; Michael, L. Evan; Wang, Aiqin; Wilbert, D.; Patel, Rajiv M.; Ferris, Jennifer; Diener, James; Allen, Mary C.; Lim, Seokchun; Syu, Li-Jyun; Verhaegen, Monique; Dlugosz, Andrzej A.

doi:10.1172/jci46307

Cited by 166 publications

(153 citation statements)

References 70 publications

Supporting

Mentioning

140

Contrasting

Unclassified

Order By: Relevance

“…In both mice and human, BCC is characterized by elevated Hh signaling and a selective upregulation of cyclin D, whereas BFH display lower expression of Hh target genes and cyclin D compared with BCC . Previous studies suggested that the level of Hh pathway activation determines the tumor phenotype Grachtchouk et al, 2011). As Sufu KO keratinocytes do not display high Hh target gene expression as DKO keratinocytes and only BFH is observed in Sufu adult epidermis KOs (Fig.…”

Section: Inactivation Of Sufu and Kif7 In Adult Epidermis Results In mentioning

confidence: 79%

“…Overexpression of Gli2 in epidermis is sufficient to initiate BCC formation and is required to maintain tumor growth (Grachtchouk et al, 2000;Hutchin et al, 2005). Moreover, previous studies suggested that the level of Hh pathway activation determines skin tumor phenotype Grachtchouk et al, 2011). Despite the importance of Gli2 in epidermal development and tumorigenesis, little is known about the underlying mechanisms that regulate Gli2.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Kif7 regulates Gli2 through Sufu-dependent and -independent functions during skin development and tumorigenesis

Nieuwenhuis

Nien

et al. 2012

Development

View full text Add to dashboard Cite

SUMMARYAbnormal activation of Hedgehog (Hh) signaling leads to basal cell carcinoma (BCC) of the skin, the most common human cancer. Gli2, the major transcriptional activator of Hh signaling, is essential for hair follicle development and its overexpression in epidermis induces BCC formation and maintains tumor growth. Despite its importance in skin development and tumorigenesis, little is known about the molecular regulation of Gli2. Sufu and Kif7 are two evolutionarily conserved regulators of Gli transcription factors. Here, we show that Sufu and Kif7 regulate Gli2 through distinct mechanisms in keratinocytes. Sufu restricts the activity of Gli2 through cytoplasmic sequestration. Kif7 possesses Sufu-dependent and -independent regulatory functions in Hh signaling: while it promotes Hh pathway activity through the dissociation of Sufu-Gli2 complex, it also contributes to the repression of Hh target genes in the absence of Sufu. Deletion of both Sufu and Kif7 in embryonic skin leads to complete loss of follicular fate. Importantly, although inactivation of Sufu or Kif7 alone in adult epidermis cannot promote BCC formation, their simultaneous deletion induces BCC. These studies establish Sufu and Kif7 as crucial components in the regulation of Gli2 localization and activity, and illustrate their overlapping functions in skin development and tumor suppression.

show abstract

Section: Inactivation Of Sufu and Kif7 In Adult Epidermis Results In mentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Kif7 regulates Gli2 through Sufu-dependent and -independent functions during skin development and tumorigenesis

Nieuwenhuis

Nien

et al. 2012

Development

View full text Add to dashboard Cite

show abstract

“…A number of studies have been directed at dissecting the cellular origin of BCC, whereby Hh signalling activity has been activated in specific epidermal and HF stem/progenitor cell compartments. Despite these studies, the BCCinitiating cell compartment remains controversial and consensus has been difficult to attain with some studies reporting BCC formation following Hh activation in a variety of HF stem cell compartments (Grachtchouk et al, 2011;Kasper et al, 2011;Peterson et al, 2015;Wang et al, 2011), and others indicating BCC potential from IFE structures (Adolphe et al, 2006;Grachtchouk et al, 2011;Villani et al, 2010;Wong and Reiter, 2011;Youssef et al, 2012;Youssef et al, 2010) M A N U S C R I P T…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Patched Receptors Sense, Interpret, and Establish an Epidermal Hedgehog Signaling Gradient

Adolphe

Junker

Lyubimova

et al. 2017

Journal of Investigative Dermatology

View full text Add to dashboard Cite

By employing the sensitivity of single molecule fluorescent in situ hybridisation (smFISH) we have precisely quantified the levels and defined the temporal and spatial distribution of Hedgehog signalling activity during embryonic skin development, and uncovered that there is a Hedgehog signalling gradient along the proximal-distal axis of developing hair follicles. In order to explore the contribution of Hedgehog receptors Ptch1 and Ptch2 in establishing the epidermal signalling gradient, we quantitated the level of pathway activity generated in Ptch1 and Ptch1;Ptch2-deficient skin and defined the contribution of each receptor to regulation of the levels of Hedgehog signalling identified in wild-type skin. Moreover, we show that both the cellular phenotype and level of pathway activity featured in Ptch1;Ptch2-deficient cells faithfully recapitulates the Peak level of endogenous Hedgehog signalling detected at the base of developing follicles, where the concentration of endogenous Shh is predicted to be highest.Taken together, these data demonstrate that both Ptch1 and Ptch2 play a crucial role in sensing the concentration of Hedgehog ligand and regulating the appropriate dose-dependent response.

show abstract

“…Furthermore, most sporadic BCCs in elderly patients have activating mutations in this pathway (22). By genetically activating this pathway in different areas of the mouse epidermis and hair follicle, characteristic types (e.g., nodular, superficial) of BCCs can be produced, thus establishing mouse models that more closely mimic human BCC (23)(24)(25)(26)(27). As reviewed in Kasper et al in this review series (4), the analysis of the critical importance of the Hedgehog pathway in BCC and of mouse models in which this pathway is activated in various cells and under various conditions (e.g., wounding) have led to new understandings of the molecular genetics and cell biology of this cancer as well as to new systemic and therapeutic approaches to target the Hedgehog pathway for patients with BCCs that are difficult to control.…”

Section: Figurementioning

confidence: 99%

Synergy of understanding dermatologic disease and epidermal biology

Stanley¹

2012

J. Clin. Invest.

View full text Add to dashboard Cite

Dermatologic disease, although seldom life threatening, can be extremely disfiguring and interfere with the quality of life. In addition, as opposed to other organs, just the aging of skin and its adnexal structure the hair follicle can result in cosmetic concerns that affect most of us. The articles in this dermatology Review Series demonstrate recent progress in understanding the cell biology and molecular pathophysiology of the epidermis and hair follicles, which harbor keratinocyte and melanocyte stem cells. They reveal a dynamic relationship between research and clinical care: knowledge of dermatologic disease has facilitated the understanding of the biology of the epidermis and, in turn, progress in basic science has informed our understanding of disease. This type of synergy is a profound strength of clinical research of the type that the JCI is dedicated to publishing. IntroductionThe Reviews in this series highlight the progress in understanding several dermatologic diseases that are particularly important because they are common and/or disfiguring. Kubo et al. (1) highlight recent major progress in understanding the pathophysiology of atopic dermatitis (Figure 1), a disease both very common (estimates are 10%-20% prevalence in children; ref.2) and potentially severe and difficult to deal with for both patients and parents. Myung and Ito (3) discuss recent progress in understanding the bulge of the hair follicle and its importance in harboring both keratinocyte and melanocyte stem cells. Understanding the cell biology of the bulge is important for dissecting the pathophysiology of skin cancer-like basal cell carcinoma (BCC) as well as the potentially disfiguring disease vitiligo (Figure 2). In addition, the melanocyte stem cell contributes to hair pigment. Insights into this stem cell may help us understand the physiologic process of the graying of hair with age. Normal graying of hair, although not a disease, is of great concern to millions of people, probably because pigment in hair is an indication of youth (Figure 3). Finally, Kasper et al. (4) and Ratushny et al. (5) discuss new aspects of the pathophysiology of skin cancers. Not only are cancers of the skin some of the most common cancers in humans, but they can be terribly disfiguring if left untreated (Figure 4).

show abstract

Basal cell carcinomas in mice arise from hair follicle stem cells and multiple epithelial progenitor populations

Cited by 166 publications

References 70 publications

Kif7 regulates Gli2 through Sufu-dependent and -independent functions during skin development and tumorigenesis

Kif7 regulates Gli2 through Sufu-dependent and -independent functions during skin development and tumorigenesis

Patched Receptors Sense, Interpret, and Establish an Epidermal Hedgehog Signaling Gradient

Synergy of understanding dermatologic disease and epidermal biology

Contact Info

Product

Resources

About