Normal Skin Cells Increase Aggressiveness of Cutaneous Melanoma by Promoting Epithelial-to-Mesenchymal Transition via Nodal and Wnt Activity

Melanoma is a lethal form of skin cancer triggered by genetic and environmental factors. Excision of early-stage, poorly aggressive melanoma often leads to a successful outcome; however, left undiagnosed these lesions can progress to metastatic disease. This research investigates whether the exposur...

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Autores principales:	Gustavo Untiveros, Lindsay Dezi, Megan Gillette, Julia Sidor, Luigi Strizzi
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	melanoma normal skin cells co-culture epithelial-to-mesenchymal transition Nodal Wnt Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/b0acb0ba4be743c2a2d75334b9b26946
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spelling	oai:doaj.org-article:b0acb0ba4be743c2a2d75334b9b269462021-11-11T17:10:36ZNormal Skin Cells Increase Aggressiveness of Cutaneous Melanoma by Promoting Epithelial-to-Mesenchymal Transition via Nodal and Wnt Activity10.3390/ijms2221117191422-00671661-6596https://doaj.org/article/b0acb0ba4be743c2a2d75334b9b269462021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11719https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Melanoma is a lethal form of skin cancer triggered by genetic and environmental factors. Excision of early-stage, poorly aggressive melanoma often leads to a successful outcome; however, left undiagnosed these lesions can progress to metastatic disease. This research investigates whether the exposure of poorly aggressive melanoma to certain normal skin cells can explain how non-metastatic melanoma becomes more aggressive while still confined to the skin. To this end, we used a serial co-culture approach to sequentially expose cells from two different, poorly aggressive human melanoma cell lines against normal cells of the skin beginning with normal melanocytes, then epidermal keratinocytes, and finally dermal fibroblasts. Protein extraction of melanoma cells occurred at each step of the co-culture sequence for western blot (WB) analysis. In addition, morphological and functional changes were assessed to detect differences between the serially co-cultured melanoma cells and non-co-cultured cells. Results show that the co-cultured melanoma cells assumed a more mesenchymal morphology and displayed a significant increase in proliferation and invasiveness compared to control or reference cells. WB analysis of protein from the co-cultured melanoma cells showed increased expression of Snail and decreased levels of E-cadherin suggesting that epithelial-to-mesenchymal transition (EMT) is occurring in these co-cultured cells. Additional WB analysis showed increased levels of Nodal protein and signaling and signs of increased Wnt activity in the co-cultured melanoma cells compared to reference cells. These data suggest that interaction between poorly aggressive melanoma cells with normal cells of the skin may regulate the transition from localized, poorly aggressive melanoma to invasive, metastatic disease via Nodal and/or Wnt induced EMT.Gustavo UntiverosLindsay DeziMegan GilletteJulia SidorLuigi StrizziMDPI AGarticlemelanomanormal skin cellsco-cultureepithelial-to-mesenchymal transitionNodalWntBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11719, p 11719 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	melanoma normal skin cells co-culture epithelial-to-mesenchymal transition Nodal Wnt Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	melanoma normal skin cells co-culture epithelial-to-mesenchymal transition Nodal Wnt Biology (General) QH301-705.5 Chemistry QD1-999 Gustavo Untiveros Lindsay Dezi Megan Gillette Julia Sidor Luigi Strizzi Normal Skin Cells Increase Aggressiveness of Cutaneous Melanoma by Promoting Epithelial-to-Mesenchymal Transition via Nodal and Wnt Activity
description	Melanoma is a lethal form of skin cancer triggered by genetic and environmental factors. Excision of early-stage, poorly aggressive melanoma often leads to a successful outcome; however, left undiagnosed these lesions can progress to metastatic disease. This research investigates whether the exposure of poorly aggressive melanoma to certain normal skin cells can explain how non-metastatic melanoma becomes more aggressive while still confined to the skin. To this end, we used a serial co-culture approach to sequentially expose cells from two different, poorly aggressive human melanoma cell lines against normal cells of the skin beginning with normal melanocytes, then epidermal keratinocytes, and finally dermal fibroblasts. Protein extraction of melanoma cells occurred at each step of the co-culture sequence for western blot (WB) analysis. In addition, morphological and functional changes were assessed to detect differences between the serially co-cultured melanoma cells and non-co-cultured cells. Results show that the co-cultured melanoma cells assumed a more mesenchymal morphology and displayed a significant increase in proliferation and invasiveness compared to control or reference cells. WB analysis of protein from the co-cultured melanoma cells showed increased expression of Snail and decreased levels of E-cadherin suggesting that epithelial-to-mesenchymal transition (EMT) is occurring in these co-cultured cells. Additional WB analysis showed increased levels of Nodal protein and signaling and signs of increased Wnt activity in the co-cultured melanoma cells compared to reference cells. These data suggest that interaction between poorly aggressive melanoma cells with normal cells of the skin may regulate the transition from localized, poorly aggressive melanoma to invasive, metastatic disease via Nodal and/or Wnt induced EMT.
format	article
author	Gustavo Untiveros Lindsay Dezi Megan Gillette Julia Sidor Luigi Strizzi
author_facet	Gustavo Untiveros Lindsay Dezi Megan Gillette Julia Sidor Luigi Strizzi
author_sort	Gustavo Untiveros
title	Normal Skin Cells Increase Aggressiveness of Cutaneous Melanoma by Promoting Epithelial-to-Mesenchymal Transition via Nodal and Wnt Activity
title_short	Normal Skin Cells Increase Aggressiveness of Cutaneous Melanoma by Promoting Epithelial-to-Mesenchymal Transition via Nodal and Wnt Activity
title_full	Normal Skin Cells Increase Aggressiveness of Cutaneous Melanoma by Promoting Epithelial-to-Mesenchymal Transition via Nodal and Wnt Activity
title_fullStr	Normal Skin Cells Increase Aggressiveness of Cutaneous Melanoma by Promoting Epithelial-to-Mesenchymal Transition via Nodal and Wnt Activity
title_full_unstemmed	Normal Skin Cells Increase Aggressiveness of Cutaneous Melanoma by Promoting Epithelial-to-Mesenchymal Transition via Nodal and Wnt Activity
title_sort	normal skin cells increase aggressiveness of cutaneous melanoma by promoting epithelial-to-mesenchymal transition via nodal and wnt activity
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/b0acb0ba4be743c2a2d75334b9b26946
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Normal Skin Cells Increase Aggressiveness of Cutaneous Melanoma by Promoting Epithelial-to-Mesenchymal Transition via Nodal and Wnt Activity

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