Cutaneous cancer stem cell maintenance is dependent on β-catenin signalling

Malanchi, Ilaria; Peinado, Héctor; Kassen, Deepika; Hussenet, Thomas; Metzger, Daniel; Chambon, Pierre; Huber, Marcel; Hohl, Daniel; Cano, Amparo; Birchmeier, Walter; Huelsken, Joerg

doi:10.1038/nature06835

Cited by 559 publications

(516 citation statements)

References 31 publications

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“…Several observations show that Wnt signaling may promote the initiation of neoplastic process in many types of epithelial tumors via modulating the activity of stem cells. 34,35,37,45,47,50,51 It is also shown that BMP signaling inhibits proliferation of adult HF stem cells, while conditional ablation of the Bmpr1a gene triggers HF stem cells to proliferate leading to tumorigenesis. 43,46,52 However, it remains to be further clarified whether noggin-dependent modulation of BMP signaling directly affects Wif1 expression in the HF stem cells thus contributing to their reprogramming toward a neoplastic phenotype, or these changes occur at the level of transient amplifying cells during their differentiation pathway toward hair matrix keratinocytes.…”

Section: Discussionmentioning

confidence: 99%

Bone Morphogenetic Protein Antagonist Noggin Promotes Skin Tumorigenesis via Stimulation of the Wnt and Shh Signaling Pathways

Sharov

Mardaryev

Sharova

et al. 2009

The American Journal of Pathology

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Bone morphogenetic proteins (BMPs) play pivotal roles in the regulation of skin development. To study the role of BMPs in skin tumorigenesis, BMP antagonist noggin was used to generate keratin 14-targeted transgenic mice. In contrast to wild-type mice, transgenic mice developed spontaneous hair follicle-derived tumors, which resemble human trichofolliculoma. Global gene expression profiles revealed that in contrast to anagen hair follicles of wild-type mice, Skin cancer is the most common cancer in the United States, Europe, and other countries, and the incidence continues to increase. 1 During the last decade, considerable progress has been achieved in identification of molecular mechanisms underlying the development of the major cutaneous cancers, such as malignant melanoma, basal cell carcinoma, and squamous cell carcinoma. 2,3 In particular, it was shown that mechanisms controlling skin development and carcinogenesis appear to be very similar, and key signaling pathways (Wnt, hedgehog, notch, transforming growth factor-␤, etc) that regulate skin development are also implicated in the pathobiology of cutaneous neoplasias [reviewed in [1][2][3][4][5] ].Bone morphogenetic protein (BMP) signaling plays pivotal roles in the control of cutaneous development and also possesses a potent antitumor activity in postnatal skin [for review see 6,7 ]. BMP signaling is activated by binding of the BMP ligands to BMP receptors (BMPRs) followed by activation of the BMP-Smad and/or BMP-MAP kinase pathways.

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Section: Discussionmentioning

confidence: 99%

Bone Morphogenetic Protein Antagonist Noggin Promotes Skin Tumorigenesis via Stimulation of the Wnt and Shh Signaling Pathways

Sharov

Mardaryev

Sharova

et al. 2009

The American Journal of Pathology

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“…Control mice had to be killed by two months of age, a time at which no Bmal1KO mice had developed the number, or size, of tumours. The growth of cutaneous squamous tumours has been shown to depend on Wnt activity in a population of CD34 1 tumour-initiating cells 36 . However, we could not detect any nuclear b-catenin, either in control or in Bmal1KO neoplastic lesions, suggesting that, in our model, tumour growth did not primarily depend on misregulated Wnt signalling ( Supplementary Fig.…”

Section: Loss Of Bmal1 Reduces Skin Tumorigenesismentioning

confidence: 99%

The circadian molecular clock creates epidermal stem cell heterogeneity

Janich

Pascual

Merlos‐Suárez

et al. 2011

Nature

282

290

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Murine epidermal stem cells undergo alternate cycles of dormancy and activation, fuelling tissue renewal. However, only a subset of stem cells becomes active during each round of morphogenesis, indicating that stem cells coexist in heterogeneous responsive states. Using a circadian-clock reporter-mouse model, here we show that the dormant hair-follicle stem cell niche contains coexisting populations of cells at opposite phases of the clock, which are differentially predisposed to respond to homeostatic cues. The core clock protein Bmal1 modulates the expression of stem cell regulatory genes in an oscillatory manner, to create populations that are either predisposed, or less prone, to activation. Disrupting this clock equilibrium, through deletion of Bmal1 (also known as Arntl) or Per1/2, resulted in a progressive accumulation or depletion of dormant stem cells, respectively. Stem cell arrhythmia also led to premature epidermal ageing, and a reduction in the development of squamous tumours. Our results indicate that the circadian clock fine-tunes the temporal behaviour of epidermal stem cells, and that its perturbation affects homeostasis and the predisposition to tumorigenesis.Epidermal stem cells ensure that skin homeostasis is maintained. Murine epidermal stem cells are located either at the permanent portion of the hair follicle-termed the bulge-and are exclusively responsible for hair cycling [1][2][3][4] ; or at the junction between the epidermis and the hair follicle (isthmus), and feed into the epidermis and sebaceous glands [5][6][7] . In addition, a continuous proliferation of basal interfollicular epidermal cells ensures daily epidermal maintenance 8 .Bulge stem cells undergo bouts of activation followed by periods of dormancy, to establish hair follicle cycling. Robust TGF-b and Bmp signals act as 'activation breaks', rendering bulge cells dormant during the resting phase of the hair cycle (telogen) [9][10][11] . At the onset of the growth phase (anagen), bulge cells respond to Wnt signals by migrating into the lower proliferative hair germ region, where they contribute to follicle growth [12][13][14][15] . Subsequently, at mid-anagen, the bulge undergoes a second round of activation, which replenishes cells lost at the onset of anagen 2,3 . However, the response of bulge stem cells to activating stimuli is a heterogeneous process, as only a subset of them become active during either stage of activation 12,13 . The nature of such niche heterogeneity is currently unknown. Importantly, perturbing the equilibrium between the responsive and non-responsive stem cell states causes tissue malfunction and increases the risk of carcinogenesis [16][17][18][19][20] .Here, we analysed the role of the molecular clock in fine-tuning the function of epidermal stem cells. The mammalian clock machinery anticipates and synchronizes vital functions related to the physiological circadian needs of the organism 21 . The core molecular clock is established by a positive limb, composed of heterodimers of the transcription fa...

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“…Canonical Wnt signaling is highly activated in cancer stem cells. 9,10 Significant efforts have been made to discover inhibitors for the key effectors of the canonical Wnt signaling pathway. 5 Small-molecule inhibitors of the enzymes Porcupine 11−13 and tankyrase 11,14 have been discovered.…”

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confidence: 99%

Structure-Based Design of 1,4-Dibenzoylpiperazines as β-Catenin/B-Cell Lymphoma 9 Protein–Protein Interaction Inhibitors

Wisniewski

Yin

Teuscher

et al. 2016

ACS Med. Chem. Lett.

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A small-molecule inhibitor with a 1,4-dibenzoylpiperazine scaffold was designed to match the critical binding elements in the β-catenin/B-cell lymphoma 9 (BCL9) protein−protein interaction interface. Inhibitor optimization led to a potent inhibitor that can disrupt the β-catenin/BCL9 interaction and exhibit 98-fold selectivity over the β-catenin/cadherin interaction. The binding mode of new inhibitors was characterized by structure−activity relationships and site-directed mutagenesis studies. Cell-based studies demonstrated that this series of inhibitors can selectively suppress canonical Wnt signaling and inhibit growth of Wnt/β-catenin-dependent cancer cells.

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Cutaneous cancer stem cell maintenance is dependent on β-catenin signalling

Cited by 559 publications

References 31 publications

Bone Morphogenetic Protein Antagonist Noggin Promotes Skin Tumorigenesis via Stimulation of the Wnt and Shh Signaling Pathways

Bone Morphogenetic Protein Antagonist Noggin Promotes Skin Tumorigenesis via Stimulation of the Wnt and Shh Signaling Pathways

The circadian molecular clock creates epidermal stem cell heterogeneity

Structure-Based Design of 1,4-Dibenzoylpiperazines as β-Catenin/B-Cell Lymphoma 9 Protein–Protein Interaction Inhibitors

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