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A novel mouse model demonstrates that oncogenic melanocyte stem cells engender melanoma resembling human disease

Sun, Qi; Lee, Wendy; Mohri, Yasuaki; Takeo, Makoto; Lim, Chae Ho; Xu, Xiaowei; Myung, Peggy; Atit, Radhika P; Taketo, M Mark; Moubarak, Rana S; Schober, Markus; Osman, Iman; Gay, Denise L; Saur, Dieter; Nishimura, Emi K; Ito, Mayumi
Melanoma, the deadliest skin cancer, remains largely incurable at advanced stages. Currently, there is a lack of animal models that resemble human melanoma initiation and progression. Recent studies using a Tyr-CreER driven mouse model have drawn contradictory conclusions about the potential of melanocyte stem cells (McSCs) to form melanoma. Here, we employ a c-Kit-CreER-driven model that specifically targets McSCs to show that oncogenic McSCs are a bona fide source of melanoma that expand in the niche, and then establish epidermal melanomas that invade into the underlying dermis. Further, normal Wnt and Endothelin niche signals during hair anagen onset are hijacked to promote McSC malignant transformation during melanoma induction. Finally, molecular profiling reveals strong resemblance of murine McSC-derived melanoma to human melanoma in heterogeneity and gene signatures. These findings provide experimental validation of the human melanoma progression model and key insights into the transformation and heterogeneity of McSC-derived melanoma.
PMCID:6828673
PMID: 31685822
ISSN: 2041-1723
CID: 4172362

Adult hair follicles keep oncogenic growth in check [Comment]

Gay, Denise; Ito, Mayumi
Recent research shows that potentially cancerous, somatic mutations can reside in normal cells. Pineda et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201907178) report on a unique management technique by hair follicle stem cells to evade tumorigenesis.
PMID: 31537713
ISSN: 1540-8140
CID: 4156262

Melanocyte stem cells in regeneration and cancer [Meeting Abstract]

Ito, M
Melanocyte stem cells (McSCs) reside in the hair follicle bulge/secondary hair germ niche where they are essential for hair pigmentation and have the potential to also regulate epidermal pigmentation. A better understanding of the molecular mechanisms that govern these stem cells holds broad implications in pigmentation disorders including hair graying, vitiligo and melanoma. We show that Wnt signaling is temporarily activated in McSCs at the onset of hair follicle regeneration and is necessary and sufficient for their differentiation. We also show that endothelin receptor B signaling promotes proliferation and differentiation of McSCs, thereby dramatically enhances regeneration of hair and epidermal melanocytes. This effect however can only be seen in the presence of active Wnt signaling that is initiated by Wnt ligand secretion from epithelial niche. Upon skin injury or UVB irradiation, Wnt signaling and Edn signaling promote McSCs to regenerate epidermal melanocytes in the skin. Finally, we show that Wnt and Edn signals, secreted during melanocyte regeneration, can be hijacked to promote McSC malignant transformation during melanoma induction
EMBASE:628190866
ISSN: 1755-148x
CID: 3957032

Hedgehog stimulates hair follicle neogenesis by creating inductive dermis during murine skin wound healing

Lim, Chae Ho; Sun, Qi; Ratti, Karan; Lee, Soung-Hoon; Zheng, Ying; Takeo, Makoto; Lee, Wendy; Rabbani, Piul; Plikus, Maksim V; Cain, Jason E; Wang, David H; Watkins, D Neil; Millar, Sarah; Taketo, M Mark; Myung, Peggy; Cotsarelis, George; Ito, Mayumi
Mammalian wounds typically heal by fibrotic repair without hair follicle (HF) regeneration. Fibrosis and regeneration are currently considered the opposite end of wound healing. This study sought to determine if scar could be remodeled to promote healing with HF regeneration. Here, we identify that activation of the Sonic hedgehog (Shh) pathway reinstalls a regenerative dermal niche, called dermal papilla, which is required and sufficient for HF neogenesis (HFN). Epidermal Shh overexpression or constitutive Smoothened dermal activation results in extensive HFN in wounds that otherwise end in scarring. While long-term Wnt activation is associated with fibrosis, Shh signal activation in Wnt active cells promotes the dermal papilla fate in scarring wounds. These studies demonstrate that mechanisms of scarring and regeneration are not distant from one another and that wound repair can be redirected to promote regeneration following injury by modifying a key dermal signal.
PMID: 30464171
ISSN: 2041-1723
CID: 3467842

Dissecting Wnt signaling for melanocyte regulation during wound healing

Sun, Qi; Rabbani, Piul; Takeo, Makoto; Lee, Soung-Hoon; Lim, Chae Ho; Noel, En-Nekema Shandi; Taketo, M Mark; Myung, Peggy; Millar, Sarah; Ito, Mayumi
Abnormal pigmentation is commonly seen in the wound scar. Despite advancements in the research of wound healing, little is known about the repopulation of melanocytes in the healed skin. Previous studies have demonstrated the capacity of melanocyte stem cells (McSCs) in the hair follicle to contribute skin epidermal melanocytes following injury in mice and humans. Here, we focused on the Wnt pathway, known to be a vital regulator of McSCs in efforts to better understand the regulation of follicle-derived epidermal melanocytes during wound healing. We showed that transgenic expression of Wnt inhibitor, Dkk1 in melanocytes reduced epidermal melanocytes in the wound scar. Conversely, forced activation of Wnt signaling by genetically stabilizing β-catenin in melanocytes increases epidermal melanocytes. Furthermore, we reveal that deletion of Wntless, a gene required for Wnt ligand secretion, within epithelial cells, results in failure in activating Wnt signaling in adjacent epidermal melanocytes. These results reveal the essential function of extrinsic Wnt ligands to initiate Wnt signaling in follicle-derived epidermal melanocytes during wound healing. Collectively, our results suggest the potential for Wnt signal regulation to promote melanocyte regeneration and provide a potential molecular window to promote proper melanocyte regeneration following wounding as well as in conditions such as vitiligo.
PMCID:6019608
PMID: 29428355
ISSN: 1523-1747
CID: 2958132

Wound regeneration deficit in rats correlates with low morphogenetic potential and distinct transcriptome profile of epidermis

Guerrero-Juarez, Christian F; Astrowski, Aliaksandr A; Murad, Rabi; Dang, Christina T; Shatrova, Vera O; Astrowskaja, Aksana; Lim, Chae Ho; Ramos, Raul; Wang, Xiaojie; Liu, Yuchen; Lee, Hye-Lim; Pham, Kim T; Hsi, Tsai-Ching; Oh, Ji Won; Crocker, Daniel; Mortazavi, Ali; Ito, Mayumi; Plikus, Maksim V
Large excisional wounds in mice prominently regenerate new hair follicles (HFs) and fat, yet humans are deficient for this regenerative behavior. Currently, wound-induced regeneration remains a clinically desirable, but only partially understood phenomenon. We show that large excisional wounds in rats, across seven strains fail to regenerate new HFs. We compared wound transcriptomes between mice and rats at the time of scab detachment, which coincides with the onset of HF regeneration in mice. In both species, wound dermis and epidermis share core dermal and epidermal transcriptional programs respectively, yet prominent inter-species differences exist. Compared to mice, rat epidermis expresses distinct transcriptional and epigenetic factors, markers of epidermal repair, hyperplasia, and inflammation, and lower levels of WNT signaling effectors and regulators. When recombined on the surface of excisional wounds with vibrissa dermal papillae, partial-thickness skin grafts containing distal pelage HF segments, but not interfollicular epidermis, readily regenerated new vibrissa-like HFs. Together, our findings establish rats as a non-regenerating rodent model for excisional wound healing and suggest that low epidermal competence and associated transcriptional profile may contribute to its regenerative deficiency. Future comparison between rat and mouse may lend further insight into the mechanism of wounding-induced regeneration and causes for its deficit.
PMCID:6059613
PMID: 29317265
ISSN: 1523-1747
CID: 2906452

Cell of origin contributes to the melanoma diversity [Meeting Abstract]

Sun, Q.; Lee, W.; Takeo, M.; Lim, C.; Xu, X.; Moubarak, R.; Myung, P.; Taketo, M.; Osman, I.; Nishimura, E.; Ito, M.
ISI:000431498600643
ISSN: 0022-202x
CID: 3132662

Defective maintenance of hair follicle stem cells through COL17A1 loss orchestrates the hair follicle aging program [Meeting Abstract]

Matsumura, H; Mohri, Y; Nguyen, T; Morinaga, H; Fukuda, M; Ito, M; Kurata, S; Hoeijmakers, J; Nishimura, EK
ISI:000410115800237
ISSN: 1523-1747
CID: 2713542

Adenosine A2a Receptor Blockade Diminishes Wnt/beta-Catenin Signaling in a Murine Model of Bleomycin-Induced Dermal Fibrosis

Zhang, Jin; Corciulo, Carmen; Liu, Hailing; Wilder, Tuere; Ito, Mayumi; Cronstein, Bruce
Adenosine A2a receptor (A2aR) stimulation promotes the synthesis of collagens I and III, and we have recently demonstrated that there is crosstalk between the A2aR and WNT/beta-catenin signaling pathway. In in vitro studies, A2aR signaling for collagen III expression was mediated by WNT/beta-catenin signaling in human dermal fibroblasts; we further verified whether the crosstalk between A2aR and Wnt/beta-catenin signaling was involved in diffuse dermal fibrosis in vivo. Wnt-signaling reporter mice (Tcf/Lef:H2B-GFP) were challenged with bleomycin and treated with the selective A2aR antagonist istradefylline (KW6002) or vehicle. Dermal fibrosis was quantitated and nuclear translocation of beta-catenin in fibroblasts was assessed by double-staining for Green fluorescent protein or dephosphorylated beta-catenin or beta-catenin phosphorylated at Ser552, and vimentin. KW6002 significantly reduced skin thickness, skinfold thickness, breaking tension, dermal hydroxyproline content, myofibroblast accumulation, and collagen alignment in bleomycin-induced dermal fibrosis. Also, there was increased expression of Tcf/Lef:H2B-GFP reporter in bleomycin-induced dermal fibrosis, an effect that was diminished by treatment with KW6002. Moreover, KW6002 significantly inhibited nuclear translocation of Tcf/Lef:H2B-GFP reporter, as well as dephosphorylated beta-catenin and beta-catenin phosphorylated at Ser552. Our work supports the hypothesis that pharmacologic blockade of A2aR inhibits the WNT/beta-catenin signaling pathway, contributing to its capacity to inhibit bleomycin-induced dermal fibrosis.
PMCID:5809334
PMID: 28667836
ISSN: 1525-2191
CID: 2614882

Critical role of WNT signaling in follicular melanocyte stem cells in adult skin [Meeting Abstract]

Sun, Q; Ito, M
Melanocyte stem cells (McSCs) reside in the hair follicle bulge/ secondary hair germ niche where they are essential for hair pigmentation and have the potential to also regulate epidermal pigmentation. A better understanding of the molecular mechanisms that govern these stem cells holds broad implications in pigmentation disorders including hair graying, vitiligo and melanoma. We show that Wnt signaling is temporarily activated in McSCs at the onset of hair follicle regeneration and is necessary for their differentiation. Nonetheless, lineage tracing of Wnt-active differentiated McSCs demonstrate that McSCs can revert back to undifferentiated McSCs following withdrawal of Wnt signal activation. This suggests that McSC differentiation driven by Wnt signaling can be reversible, and temporal Wnt activation in McSCs does not deprive their self-renewing capacity. This ability of McSCs to oscillate between the differentiated and undifferentiated/stem cell states is not prevented when they differentiate into mature melanocytes after UVB irradiation. In aged mice, this process is compromised due to the failure to cease Wnt signaling, leading to ectopic McSC differentiation and a failure to return to their undifferentiated state, ultimately resulting in their loss. Upon induction of melanoma forming mutations, McSCs exhibit the potential to form melanoma. The tumorigenic potential of McSCs is regulated by Wnt signaling. Our results show the critical function of Wnt signaling in governing behavior of McSCs in adult skin during normal tissue homeostasis and melanoma
EMBASE:618287957
ISSN: 1755-1471
CID: 2710272