Beta-catenin inhibits melanocyte migration but induces melanoma metastasis

Gallagher, Stuart J.; Rambow, Florian; Kumasaka, Mayuko Y.; Champeval, Delphine; Bellacosa, Alfonso; Delmas, Véronique; Larue, Lionel

doi:10.1038/onc.2012.229

Cited by 98 publications

(108 citation statements)

References 32 publications

(55 reference statements)

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“…4 and 5). Beta-catenin has previously been experimentally associated with metastasis in melanoma (15,16). Of the two cell populations metastasizing in patient C, each acquired a different, known activating mutation in beta-catenin (S33P and G34E), consistent with a necessity for CTNNB1 activation in forming metastases.…”

Section: Primarymentioning

confidence: 82%

“…It is remarkable that known activating mutations in β-catenin emerged multiple times among these late-arising variants associated with metastases. Activation of the wingless-type mouse mammary tumor virus integration site (WNT) signaling pathway (e.g., by β-catenin mutations) has also been implicating in promoting metastatic potential in mouse models of melanoma (15,16). The reconstructed evolution of metastatic dissemination in patient C is depicted in Fig.…”

Section: Metastases Can Be Founded By Multiple Genetically Distinct mentioning

confidence: 99%

See 1 more Smart Citation

Phylogenetic analyses of melanoma reveal complex patterns of metastatic dissemination

Sanborn¹,

Chung

Purdom

et al. 2015

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

153

133

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Melanoma is difficult to treat once it becomes metastatic. However, the precise ancestral relationship between primary tumors and their metastases is not well understood. We performed whole-exome sequencing of primary melanomas and multiple matched metastases from eight patients to elucidate their phylogenetic relationships. In six of eight patients, we found that genetically distinct cell populations in the primary tumor metastasized in parallel to different anatomic sites, rather than sequentially from one site to the next. In five of these six patients, the metastasizing cells had themselves arisen from a common parental subpopulation in the primary, indicating that the ability to establish metastases is a late-evolving trait. Interestingly, we discovered that individual metastases were sometimes founded by multiple cell populations of the primary that were genetically distinct. Such establishment of metastases by multiple tumor subpopulations could help explain why identical resistance variants are identified in different sites after initial response to systemic therapy. One primary tumor harbored two subclones with different oncogenic mutations in CTNNB1, which were both propagated to the same metastasis, raising the possibility that activation of wingless-type mouse mammary tumor virus integration site (WNT) signaling may be involved, as has been suggested by experimental models.A s in many other solid tumors, melanoma metastases often first present in lymph nodes in the draining area of the primary, whereas distant metastases tend to appear later (1). The conclusion that melanoma follows a linear progression from primary tumor to regional to distant metastases has supported preemptive surgical removal of regional lymph nodes with curative intent (2). However, several observations suggest that distant metastases are seeded early, contemporaneously with regional metastases. Patients who undergo resection of lymph node basins harboring metastasis do not experience a significantly extended life expectancy (3, 4). Furthermore, circulating melanoma cells were detected in the blood of 26% of patients who only have metastases detected regionally (5, 6).Melanoma, like other cancers, arises and evolves through the accumulation of genetic alterations within tumor cells (7-9). Comparing somatic mutations in primary tumor and regional and distant metastases from the same patient can provide insight into the phylogenetic relationships between these distinct tumor cell populations and the order of metastatic dissemination (8, 10). These analyses may also establish whether cells in the primary tumor that metastasize acquired this ability to disseminate and seed other anatomic sites by a newly acquired genetic alteration, or whether metastatic colonization is simply a stochastic process of which all cells in the primary are capable but few succeed.Using whole-exome sequencing (for discovery) and targeted sequencing (for validation), we analyzed mutation patterns of primary melanomas and two or more metastases in each of e...

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Section: Primarymentioning

confidence: 82%

Section: Metastases Can Be Founded By Multiple Genetically Distinct mentioning

confidence: 99%

Phylogenetic analyses of melanoma reveal complex patterns of metastatic dissemination

Sanborn¹,

Chung

Purdom

et al. 2015

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

153

133

View full text Add to dashboard Cite

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“…Forced expression of β-catenin in melanoma cells drives cell proliferation (27), and expression of β-catenin and/or β-catenin transcriptional targets is required for proliferation of melanoma cell lines (28). In the mouse, activated Wnt signaling promotes melanoma metastasis to the lymph nodes and lungs (29,30). However, many human benign nevi are positive for nuclear β-catenin, and expression decreases on progression to metastatic melanoma (31).…”

mentioning

confidence: 99%

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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“…In this case, β-catenin cooperates with PTEN loss and BRAF V600E to promote primary tumor and metastasis, but the mechanism was not enlightened [1]. In other study, activation of β-catenin signaling increased metastatic potential in NRAS-driven melanoma in mice, although it repressed cell migration, indicating that β-catenin inhibits the initial steps of metastasis, as cell migration, but can be involved in the latest steps of this process [100].…”

Section: Wnt (β-Catenin and Wnts)mentioning

confidence: 98%

“…Therefore, β-catenin effects on melanoma metastasis are still not fully understood and may depend on cellular context [100]. Some state that WNT signaling via the canonical pathway, which involves β-catenin, is associated with a less metastatic phenotype, while the noncanonical pathway, involving Wnt5A, would be related with increased malignancy [6].…”

Section: Wnt (β-Catenin and Wnts)mentioning

confidence: 99%