Stem cell spreading dynamics intrinsically differentiate acral melanomas from nevi

Eshiba, Sally; Namiki, Takeshi; Mohri, Yasuaki; Aida, Tomomi; Serizawa, Naotaka; Shibata, Takakazu; Morinaga, Hironobu; Nanba, Daisuke; Hiraoka, Yuichi; Miura, Keiko; Tanaka, Masaru; Uhara, Hisashi; Yokozeki, Hiroo; Saida, Toshiaki; Nishimura, Emi K.

doi:10.1016/j.celrep.2021.109492

Cited by 12 publications

(19 citation statements)

References 70 publications

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“…Since there are few available animal models of acral melanoma 25 , we used a rapid transgenic zebrafish system to model these potential drivers in vivo. Using the melanocyte-specific mitfa promoter, we created mosaic (F 0 ) transgenic fish expressing acral melanoma drivers (CRKL, GAB2, TERT) with NF1 deletion and then compared them with a previously developed cutaneous melanoma model (BRAF V600E ;p53 −/− ) or to wild-type melanocytes (Fig.…”

Section: Acral Genes Drive Tumours To Acral Sitesmentioning

confidence: 99%

Anatomic position determines oncogenic specificity in melanoma

Weiss

Hunter

Cruz

et al. 2022

Nature

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Oncogenic alterations to DNA are not transforming in all cellular contexts 1,2 . This may be due to pre-existing transcriptional programmes in the cell of origin. Here we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype arises on the palms of the hands, soles of the feet or under the nails 3 . We sequenced the DNA of cutaneous and acral melanomas from a large cohort of human patients and found a specific enrichment for BRAF mutations in cutaneous melanoma and enrichment for CRKL amplifications in acral melanoma. We modelled these changes in transgenic zebrafish models and found that CRKL-driven tumours formed predominantly in the fins of the fish. The fins are the evolutionary precursors to tetrapod limbs, indicating that Weiss et al.

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Section: Acral Genes Drive Tumours To Acral Sitesmentioning

confidence: 99%

Anatomic position determines oncogenic specificity in melanoma

Weiss

Hunter

Cruz

et al. 2022

Nature

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“…Since there are few widely available animal models of acral melanoma 30 , we used a rapid transgenic zebrafish system to model these potential drivers in vivo . Using the melanocyte-specific mitfa promoter, we created mosaic (F0) transgenic animals expressing putative acral melanoma drivers (CRKL, GAB2, TERT and NF1 loss) and then compared this to a previously developed cutaneous melanoma model (BRAF V600E ;p53-/-) or to wildtype melanocytes (Fig.…”

Section: Resultsmentioning

confidence: 99%

Anatomic position determines oncogenic specificity in melanoma

Weiss

Hunter

Tagore

et al. 2020

Preprint

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SummaryOncogenic alterations to DNA are not transforming in all cellular contexts1,2. This may be due to pre-existing transcriptional programs in the cell of origin. Here, we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype has a unique tropism for the limbs, specifically the hands and feet3. We sequenced the DNA of cutaneous and acral melanomas from a large cohort of human patients and found a specific enrichment for BRAF mutations in cutaneous melanoma but CRKL amplifications in acral melanoma. We modeled these changes in transgenic zebrafish models and found that CRKL-driven tumors predominantly formed in the fins of the fish. The fins are the evolutionary precursors to tetrapod limbs, indicating that melanocytes in these acral locations may be uniquely susceptible to CRKL. RNA profiling of these fin/limb melanocytes, compared to body melanocytes, revealed a positional identity gene program typified by posterior HOX13 genes. This positional gene program synergized with CRKL to drive tumors at acral sites. Abrogation of this CRKL-driven program eliminated the anatomic specificity of acral melanoma. These data suggest that the anatomic position of the cell of origin endows it with a unique transcriptional state that makes it susceptible to only certain oncogenic insults.

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“…NM and SSM arise from melanocytes determined from the first wave of melanoblasts, and one could speculate that ALM arises from melanocytes derived from the second wave of melanoblasts. This hypothesis has to be put in perspective with a recent work showing that ALM may emerge from melanocyte stem cells located in sweat glands ( Eshiba et al, 2021 ). Although sun exposure is a well-established cause for melanoma development, the soles and palms are non-sun-exposed regions, raising the issue of the importance of the embryonic origin of melanocytes in melanomagenesis and how this may influence their aggressiveness when transformed.…”

Section: Discussionmentioning

confidence: 99%

Stabilization of β-catenin promotes melanocyte specification at the expense of the Schwann cell lineage

et al. 2022

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The canonical Wnt/β-catenin pathway governs a multitude of developmental processes in various cell lineages, including the melanocyte lineage. Indeed, β-catenin regulates Mitf-M transcription, the master regulator of this lineage. The first wave of melanocytes to colonize the skin is directly derived from neural crest cells, while the second wave of melanocytes is derived from Schwann-cell precursors (SCPs). We investigated the influence of β-catenin in the development of melanocytes of the first and second waves by generating mice expressing a constitutively active form of β-catenin in cells expressing tyrosinase. Constitutive activation of β-catenin did not affect the development of truncal melanoblasts but led to marked hyperpigmentation of the paws. By activating β-catenin at various stages of development (E8.5-E11.5), we showed that the activation of β-catenin in bipotent SCPs favored melanoblast specification at the expense of Schwann cells in the limbs within a specific temporal window. Furthermore, in vitro hyperactivation of the Wnt/β-catenin pathway, which is required for melanocyte development, induces activation of Mitf-M, in turn repressing FoxD3 expression. In conclusion, β-catenin overexpression promotes SCP cell fate decisions towards the melanocyte lineage.

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Stem cell spreading dynamics intrinsically differentiate acral melanomas from nevi

Cited by 12 publications

References 70 publications

Anatomic position determines oncogenic specificity in melanoma

Anatomic position determines oncogenic specificity in melanoma

Anatomic position determines oncogenic specificity in melanoma

Stabilization of β-catenin promotes melanocyte specification at the expense of the Schwann cell lineage

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