Metastasizing Melanoma Formation Caused by Expression of Activated N-RasQ61K on an INK4a-Deficient Background

Ackermann, Julien; Frutschi, Manon; Kaloulis, Kostas; Mckee, Thomas Alexander; Trumpp, Andreas; Beermann, Friedrich

doi:10.1158/0008-5472.can-04-2970

Cited by 269 publications

(324 citation statements)

References 36 publications

(43 reference statements)

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“…Conceivably, such a process cannot be adequately assessed in cell lines derived from already established metastases, such as those that have been used in previous studies of SOX2 in melanoma. Therefore, we sought to address the role of Sox2 in the Tyr::NRas Q61K Ink4a -/-mouse model that recapitulates all aspects of melanoma formation, including tumor initiation from benign melanocytic cells, primary tumor growth, dissemination of metastatic cells, and secondary tumor growth at distant sites 25,26 .…”

Section: Sox2 Is Expressed In Murine Melanoma But Not Critical For Sumentioning

confidence: 99%

“…Tyr::NRas Q61K Ink4a -/-mice reliably develop skin melanoma within 6 months of age and often present with metastases in lymph nodes, lungs and liver 25,26 . Of note, both control as well as the Sox2 cKO mice developed a macroscopically visible hyperplasia and primary melanomas (Figure 4a, b).…”

Section: Sox2 Is Dispensable For Primary Tumor and Metastasis Formationmentioning

confidence: 99%

“…To shed light on this issue, we decided to analyse the role of Sox2 during melanoma oncogenesis using knockout approaches that fully block Sox2 function and, in particular, using a genetically engineered mouse melanoma model, in which metastatic melanoma spontaneously develops within an intact stromal environment 25,26 . However, conditional Sox2 inactivation did not affect tumor initiation and progression, speaking against an essential function for this transcription factor in melanoma.…”

Section: Introductionmentioning

confidence: 99%

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Sox2 is dispensable for primary melanoma and metastasis formation

et al. 2017

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Tumor initiation and metastasis formation in many cancers have been associated with emergence of a gene expression program normally active in embryonic or organ-specific stem cells. In particular, the stem cell transcription factor Sox2 is not only expressed in a variety of tumors, but is also required for their formation. Melanoma, the most aggressive skin tumor, derives from melanocytes that during development originate from neural crest stem cells. While neural crest stem cells do not express Sox2, expression of this transcription factor has been reported in melanoma. However, the role of Sox2 in melanoma is controversial. To study the requirement of Sox2 for melanoma formation, we therefore performed CRISPR-Cas9-mediated gene inactivation in human melanoma cells. In addition, we conditionally inactivated Sox2 in a genetically engineered mouse model, in which melanoma spontaneously develops in the context of an intact stroma and immune system. Surprisingly, in both models, loss of Sox2 did neither affect melanoma initiation, nor growth, nor metastasis formation. The lack of a tumorigenic role of Sox2 in melanoma might reflect a distinct stem cell program active in neural crest stem cells and during melanoma formation.

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Section: Sox2 Is Expressed In Murine Melanoma But Not Critical For Sumentioning

confidence: 99%

Section: Sox2 Is Dispensable For Primary Tumor and Metastasis Formationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sox2 is dispensable for primary melanoma and metastasis formation

et al. 2017

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“…Specifically, an activated H-RAS transgene, together with inactivating mutations in Ink4a, Arf, and/or p53 promotes development of nonmetastatic melanomas (Chin et al 1997;Bardeesy et al 2001;Sharpless et al 2003). In contrast, when targeted to the melanocytic compartment, an activated N-RAS transgene and Ink4a/Arf deficiency drive cutaneous melanomas with high penetrance and short latency, as well as metastatic spread to lymph nodes and other distal sites (e.g., lung and liver) in a third of the cases (Ackermann et al 2005).…”

Section: The Ras Family Of Proto-oncogenes: H-ras N-ras and K-rasmentioning

confidence: 99%

Malignant melanoma: genetics and therapeutics in the genomic era

2006

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Cell for cell, probably no human cancer is as aggressive as melanoma. It is among a handful of cancers whose dimensions are reported in millimeters. Tumor thickness approaching 4 mm presents a high risk of metastasis, and a diagnosis of metastatic melanoma carries with it an abysmal median survival of 6-9 mo. What features of this malignancy account for such aggressive behavior? Is it the migratory history of its cell of origin or the programmed adaptation of its differentiated progeny to environmental stress, particularly ultraviolet radiation? While the answers to these questions are far from complete, major strides have been made in our understanding of the cellular, molecular, and genetic underpinnings of melanoma. More importantly, these discoveries carry profound implications for the development of therapies focused directly at the molecular engines driving melanoma, suggesting that we may have reached the brink of an unprecedented opportunity to translate basic science into clinical advances. In this review, we attempt to summarize our current understanding of the genetics and biology of this disease, drawing from expanding genomic information and lessons from development and genetically engineered mouse models. In addition, we look forward toward how these new insights will impact on therapeutic options for metastatic melanoma in the near future. The diseaseMelanomas most often arise within epidermal melanocytes of the skin, although they can also derive from noncutaneous melanocytes such as those lining the choroidal layer of the eye, GI and GU mucosal surfaces, or the meninges. Melanoma is also among the more common causes of "metastatic cancer of unknown primary," which may reflect either a propensity to arise in unexpected sites along the neural crest migratory route, or rapid growth of poorly differentiated lesions arising from indolent or unrecognized cutaneous primary lesions. Clinical staging for primary cutaneous melanoma employs measurements of thickness (in millimeters), presence of ulceration, penetration through cutaneous layers, mitotic rate, evidence of "in transit" metastasis, tumor spread to draining lymph nodes, and evidence of distant metastasis. Management issues in melanoma can be classified in terms of prevention, diagnosis, local disease management, and treatment of metastatic disease.In view of the epidemiological and emerging experimental evidence linking melanoma incidence to UV exposure and skin phototype, prevention and screening strategies represent key areas for reduction of disease incidence and severity. For most cutaneous melanomas in the so-called radial growth phase (e.g., thin melanomas), surgical removal affords curative treatment. In contrast, a significant fraction of patients diagnosed with intermediate-thickness (2-4 mm) cutaneous melanoma eventually succumb to recurrence at regional or distant sites.Critical biological questions facing the melanoma research community include: (1) What genetic and environmental factors contribute to and/or modulate risk of melanom...

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“…Moreover, mutations in the INK4a locus that lead to inactivation of tumor suppressor genes are most common in human melanoma. In a melanoma mouse model, overexpression of the Nras Q61K oncogene under the control of tyrosinase promoter, in combination with loss of INK4a, results in melanoma formation with a high penetrance (>90%) at around 6 months of age 4 . In contrast, INK4a -/-mice barely develop melanoma 5 .…”

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confidence: 99%

Sox10 promotes the formation and maintenance of giant congenital naevi and melanoma

et al. 2012

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Giant congenital naevi are pigmented childhood lesions that frequently lead to melanoma, the most aggressive skin cancer. The mechanisms underlying this malignancy are largely unknown, and there are no effective therapies. Here we describe a mouse model for giant congenital naevi and show that naevi and melanoma prominently express Sox10, a transcription factor crucial for the formation of melanocytes from the neural crest. Strikingly, Sox10 haploinsufficiency counteracts Nras(Q61K)-driven congenital naevus and melanoma formation without affecting the physiological functions of neural crest derivatives in the skin. Moreover, Sox10 is also crucial for the maintenance of neoplastic cells in vivo. In human patients, virtually all congenital naevi and melanomas are SOX10 positive. Furthermore, SOX10 silencing in human melanoma cells suppresses neural crest stem cell properties, counteracts proliferation and cell survival, and completely abolishes in vivo tumour formation. Thus, SOX10 represents a promising target for the treatment of congenital naevi and melanoma in human patients.

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Metastasizing Melanoma Formation Caused by Expression of Activated N-RasQ61K on an INK4a-Deficient Background

Abstract: In human cutaneous malignant melanoma, a predominance of activated mutations in the N-ras gene has been documented. To obtain a mouse model most closely mimicking the human disease, a transgenic mouse line was generated by targeting expression of dominant-active human N-ras (N

Cited by 269 publications

References 36 publications

Sox2 is dispensable for primary melanoma and metastasis formation

Sox2 is dispensable for primary melanoma and metastasis formation

Malignant melanoma: genetics and therapeutics in the genomic era

Sox10 promotes the formation and maintenance of giant congenital naevi and melanoma

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