β-Catenin induces immortalization of melanocytes by suppressing <i>p16<sup>INK4a</sup></i> expression and cooperates with N-Ras in melanoma development

Delmas, Véronique; Beermann, Friedrich; Martinozzi, Silvia; Carreira, Suzanne; Ackermann, Julien; Kumasaka, Mayuko Y.; Denat, Laurence; Goodall, Jane; Luciani, Flavie; Virós, Amaya; Demirkan, Neşe Çallı; Bastian, Boris C.; Goding, Colin R.; Larue, Lionel

doi:10.1101/gad.450107

Cited by 297 publications

(300 citation statements)

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“…Many human melanomas exhibit activated Wnt signaling (18,24,25), and Larue and coworkers previously showed that a stabilized β-catenin allele drives escape from N-RAS Q61K -induced senescence and ultimately progression to melanoma (18). To date, we have not observed melanoma in any of our Tyr-Cre APC fl.fl /Tyr-N-RAS Q61K mice.…”

Section: Discussionmentioning

confidence: 60%

“…Moreover, Larue and coworkers (18) demonstrated that activation of Wnt signaling in mouse melanocytes is able to bypass senescence by β-catenin-mediated repression of the tumor suppressor, p16. Here we have further analyzed the regulation and function of Wnt signaling in senescent human melanocytes in vitro, in human tissues, and in a mouse model.…”

Section: Significancementioning

confidence: 99%

“…Even so, about 25% of melanomas are thought to arise in association with a preexisting nevus (14,15). Inactivation of PTEN and p16 and activation of Wnt signaling are each thought to contribute to nevus to melanoma progression (16)(17)(18)(19). Here we investigated senescence in melanocytes in vitro and in nevi, with a view to better understand both nevus formation and progression to melanoma.…”

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confidence: 99%

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Wnt signaling potentiates nevogenesis

Pawlikowski

McBryan

Tuyn

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway (senescence-associated secretory phenotype). Cellular senescence is also a tumor suppressor mechanism, to which both proliferation arrest and senescence-associated secretory phenotype are thought to contribute. The melanocytes within benign human nevi are a paradigm for tumor-suppressive senescent cells in a premalignant neoplasm. Here a comparison of proliferating and senescent melanocytes and melanoma cell lines by RNA sequencing emphasizes the importance of senescenceassociated proliferation arrest in suppression of transformation. Previous studies showed that activation of the Wnt signaling pathway can delay or bypass senescence. Consistent with this, we present evidence that repression of Wnt signaling contributes to melanocyte senescence in vitro. Surprisingly, Wnt signaling is active in many senescent human melanocytes in nevi, and this is linked to histological indicators of higher proliferative and malignant potential. In a mouse, activated Wnt signaling delays senescenceassociated proliferation arrest to expand the population of senescent oncogene-expressing melanocytes. These results suggest that Wnt signaling can potentiate nevogenesis in vivo by delaying senescence. Further, we suggest that activated Wnt signaling in human nevi undermines senescence-mediated tumor suppression and enhances the probability of malignancy.

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Section: Discussionmentioning

confidence: 60%

Section: Significancementioning

confidence: 99%

mentioning

confidence: 99%

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Wnt signaling potentiates nevogenesis

Pawlikowski

McBryan

Tuyn

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Finally, TCF-bcat can also directly repress transcription (Hoverter and Waterman 2008); targets include decapentaplegic in fly imaginal discs (Theisen et al 2007), E-cadherin in mouse keratinocytes (Jamora et al 2003), and p16INK4a in melanomas (Delmas et al 2007). In these cases, TCF acts through traditional sites, but TCF-Arm repression of Ugt36Bc in fly hemocytes occurs through highly divergent sites .…”

Section: Into the Nucleus-target Gene Regulation By Bcat/armmentioning

confidence: 99%

Wnt Signaling from Development to Disease: Insights from Model Systems

Cadigan¹,

Peifer²

2009

Cold Spring Harbor Perspectives in Biology

275

259

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One of the early surprises in the study of cell adhesion was the discovery that b-catenin plays dual roles, serving as an essential component of cadherin-based cell -cell adherens junctions and also serving as the key regulated effector of the Wnt signaling pathway. Here, we review our current model of Wnt signaling and discuss how recent work using model organisms has advanced our understanding of the roles Wnt signaling plays in both normal development and in disease. These data help flesh out the mechanisms of signaling from the membrane to the nucleus, revealing new protein players and providing novel information about known components of the pathway.

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“…After BRAF , which harbors an activating mutation in 40% to 50% of cutaneous melanomas, NRAS is mutated in approximately 20% of tumors ( 1,2 ). Although a mouse model of melanoma driven by expression of BRAF V600E in the absence of other mutations has been developed, current NRAS-driven models rely on concomitant mutations in tumor suppressor genes (3)(4)(5). In this issue of Cancer Discovery , Pedersen and colleagues ( 6 ) show that melanocytic expression of activated NRAS results in melanoma of a quite unexpected type.…”

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confidence: 99%

A Model for Primary Melanoma of the CNS Implicates NRAS

Ciarlo¹,

Zon²

2013

Cancer Discovery

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Summary :In this issue of Cancer Discovery , Pedersen and colleagues present the fi rst mouse model of primary CNS melanoma, which arises when oncogenic NRAS is expressed from the endogenous Nras promoter in melanocytes during embryogenesis. In support of this model, two pediatric cases of NRAS -mutant primary melanoma of the CNS are identifi ed. Cancer Discov; 3(4); 382-3. ©2013 AACR.See related article by Pedersen et al., p. 458 (6).Melanoma can be subdivided into categories based on body location, and some characteristic presentations are exceedingly rare. NRAS is the second most commonly mutated gene in cutaneous melanoma, the most prevalent form of the disease. After BRAF , which harbors an activating mutation in 40% to 50% of cutaneous melanomas, NRAS is mutated in approximately 20% of tumors ( 1, 2 ). Although a mouse model of melanoma driven by expression of BRAF V600E in the absence of other mutations has been developed, current NRAS-driven models rely on concomitant mutations in tumor suppressor genes ( 3-5 ). In this issue of Cancer Discovery , Pedersen and colleagues ( 6 ) show that melanocytic expression of activated NRAS results in melanoma of a quite unexpected type. Here, they present the fi rst model for pediatric primary melanoma of the central nervous system (CNS), a rare but deadly disease.Primary melanoma of the CNS originates from melanocytes of the leptomeninges. Patients can present with intracranial hypertension, neurologic defi cits, subarachnoid hemorrhage, and seizures ( 7 ). Primary melanoma of the CNS in children occurs primarily in patients with neurocutaneous melanosis (NCM), a rare nonhereditary syndrome characterized by giant or multiple congenital melanocytic nevi (CMN; ref. 7 ). Although clinical data are limited, primary melanoma of the CNS in children has a poor prognosis. One study identifi ed 5 children over the course of 13 years with primary melanoma of the leptomeninges, all of whom died within 8 months of initial presentation ( 8 ). By expressing oncogenic NRAS in mouse melanocytes during embryonic development, Pedersen and colleagues ( 6 ) were able to recapitulate the pathology of CNS melanoma, with particular relevance to pediatric cases.To develop an NRAS-driven model of melanoma, Pedersen and colleagues ( 6 ) expressed NRAS G12D at physiologic levels in a spatially and temporally controlled manner. They did this by inserting a loxP -STOP-loxP cassette followed by NRAS G12D ( Nras LSL-G12D ) into the endogenous Nras locus. Tamoxifenactivated Cre recombinase, expressed in melanocytes using the tyrosinase promoter, allowed for stop codon excision and expression of NRAS G12D at 2 months of age by painting the backs of mice with tamoxifen. For expression during embryogenesis, the authors used unmodifi ed Cre recombinase.Surprisingly, expression of NRAS G12D during embryogenesis resulted in primary melanoma of the CNS, manifesting in neurologic symptoms such as hyperreactivity and motor dysfunction at a median of 4 months of age in Nras LSL-G12D homozygous mice and 12.5...

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β-Catenin induces immortalization of melanocytes by suppressing p16^INK4a expression and cooperates with N-Ras in melanoma development

Cited by 297 publications

References 60 publications

Wnt signaling potentiates nevogenesis

Wnt signaling potentiates nevogenesis

Wnt Signaling from Development to Disease: Insights from Model Systems

A Model for Primary Melanoma of the CNS Implicates NRAS

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β-Catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development

Cited by 297 publications

References 60 publications

Wnt signaling potentiates nevogenesis

Wnt signaling potentiates nevogenesis

Wnt Signaling from Development to Disease: Insights from Model Systems

A Model for Primary Melanoma of the CNS Implicates NRAS

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β-Catenin induces immortalization of melanocytes by suppressing p16^INK4a expression and cooperates with N-Ras in melanoma development