Role of the Skin Microenvironment in Melanomagenesis: Epidermal Keratinocytes and Dermal Fibroblasts Promote BRAF Oncogene-Induced Senescence Escape in Melanocytes
<i>BRAF<sup>V600E</sup></i> is the most common mutation driver in melanoma. This mutation is known to cause a brief burst of proliferation followed by growth arrest and senescence, which prevent an uncontrolled cell proliferation. This phenomenon is known as oncogene-induced...
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| Language: | English |
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MDPI AG
2022-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/5/1233 |
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| author | Shreyans Sadangi Katarina Milosavljevic Edgardo Castro-Perez Marcos Lares Mithalesh Singh Sarah Altameemi David J. Beebe Jose M. Ayuso Vijayasaradhi Setaluri |
| author_facet | Shreyans Sadangi Katarina Milosavljevic Edgardo Castro-Perez Marcos Lares Mithalesh Singh Sarah Altameemi David J. Beebe Jose M. Ayuso Vijayasaradhi Setaluri |
| author_sort | Shreyans Sadangi |
| collection | DOAJ |
| description | <i>BRAF<sup>V600E</sup></i> is the most common mutation driver in melanoma. This mutation is known to cause a brief burst of proliferation followed by growth arrest and senescence, which prevent an uncontrolled cell proliferation. This phenomenon is known as oncogene-induced senescence (OIS) and OIS escape is thought to lead to melanomagenesis. Much attention has been focused on the melanocyte-intrinsic mechanisms that contribute to senescence escape. Additional genetic events such as the loss of tumor suppressor <i>PTEN</i> and/or epigenetic changes that contribute to senescence escape have been described. However, the role of the skin microenvironment—specifically, the role of epidermal keratinocytes—on melanomagenesis is not fully understood. In this study, we employ a microfluidic platform to study the interaction between melanocytes expressing the <i>BRAF<sup>V600E</sup></i> mutation as well as keratinocytes and dermal fibroblasts. We demonstrate that keratinocytes suppress senescence-related genes and promote the proliferation of transformed melanocytes. We also show that a keratinocyte-conditioned medium can alter the secretion of both pro- and anti-tumorigenic factors by transformed melanocytes. In addition, we show that melanocytes and keratinocytes from donors of white European and black African ancestry display different crosstalks; i.e., white keratinocytes appear to promote a more pro-tumorigenic phenotype compared with black keratinocytes. These data suggest that keratinocytes exert their influence on melanomagenesis both by suppressing senescence-related genes in melanocytes and by affecting the balance of the melanocyte-secreted factors that favor tumorigenesis. |
| first_indexed | 2024-03-09T20:45:52Z |
| format | Article |
| id | doaj.art-96e1f94a0af3497393b697be3f2b3def |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T20:45:52Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-96e1f94a0af3497393b697be3f2b3def2023-11-23T22:47:52ZengMDPI AGCancers2072-66942022-02-01145123310.3390/cancers14051233Role of the Skin Microenvironment in Melanomagenesis: Epidermal Keratinocytes and Dermal Fibroblasts Promote BRAF Oncogene-Induced Senescence Escape in MelanocytesShreyans Sadangi0Katarina Milosavljevic1Edgardo Castro-Perez2Marcos Lares3Mithalesh Singh4Sarah Altameemi5David J. Beebe6Jose M. Ayuso7Vijayasaradhi Setaluri8Department of Dermatology, University of Wisconsin-Madison, Madison, WI 53705, USADepartment of Dermatology, University of Wisconsin-Madison, Madison, WI 53705, USADepartment of Dermatology, University of Wisconsin-Madison, Madison, WI 53705, USADepartment of Dermatology, University of Wisconsin-Madison, Madison, WI 53705, USADepartment of Dermatology, University of Wisconsin-Madison, Madison, WI 53705, USADepartment of Dermatology, University of Wisconsin-Madison, Madison, WI 53705, USADepartment of Pathology and Laboratory Medicine, University of Wisconsin, 1111 Highland Ave., Madison, WI 53705, USADepartment of Dermatology, University of Wisconsin-Madison, Madison, WI 53705, USADepartment of Dermatology, University of Wisconsin-Madison, Madison, WI 53705, USA<i>BRAF<sup>V600E</sup></i> is the most common mutation driver in melanoma. This mutation is known to cause a brief burst of proliferation followed by growth arrest and senescence, which prevent an uncontrolled cell proliferation. This phenomenon is known as oncogene-induced senescence (OIS) and OIS escape is thought to lead to melanomagenesis. Much attention has been focused on the melanocyte-intrinsic mechanisms that contribute to senescence escape. Additional genetic events such as the loss of tumor suppressor <i>PTEN</i> and/or epigenetic changes that contribute to senescence escape have been described. However, the role of the skin microenvironment—specifically, the role of epidermal keratinocytes—on melanomagenesis is not fully understood. In this study, we employ a microfluidic platform to study the interaction between melanocytes expressing the <i>BRAF<sup>V600E</sup></i> mutation as well as keratinocytes and dermal fibroblasts. We demonstrate that keratinocytes suppress senescence-related genes and promote the proliferation of transformed melanocytes. We also show that a keratinocyte-conditioned medium can alter the secretion of both pro- and anti-tumorigenic factors by transformed melanocytes. In addition, we show that melanocytes and keratinocytes from donors of white European and black African ancestry display different crosstalks; i.e., white keratinocytes appear to promote a more pro-tumorigenic phenotype compared with black keratinocytes. These data suggest that keratinocytes exert their influence on melanomagenesis both by suppressing senescence-related genes in melanocytes and by affecting the balance of the melanocyte-secreted factors that favor tumorigenesis.https://www.mdpi.com/2072-6694/14/5/1233melanomatumor microenvironmentsenescencemicrofluidics |
| spellingShingle | Shreyans Sadangi Katarina Milosavljevic Edgardo Castro-Perez Marcos Lares Mithalesh Singh Sarah Altameemi David J. Beebe Jose M. Ayuso Vijayasaradhi Setaluri Role of the Skin Microenvironment in Melanomagenesis: Epidermal Keratinocytes and Dermal Fibroblasts Promote BRAF Oncogene-Induced Senescence Escape in Melanocytes Cancers melanoma tumor microenvironment senescence microfluidics |
| title | Role of the Skin Microenvironment in Melanomagenesis: Epidermal Keratinocytes and Dermal Fibroblasts Promote BRAF Oncogene-Induced Senescence Escape in Melanocytes |
| title_full | Role of the Skin Microenvironment in Melanomagenesis: Epidermal Keratinocytes and Dermal Fibroblasts Promote BRAF Oncogene-Induced Senescence Escape in Melanocytes |
| title_fullStr | Role of the Skin Microenvironment in Melanomagenesis: Epidermal Keratinocytes and Dermal Fibroblasts Promote BRAF Oncogene-Induced Senescence Escape in Melanocytes |
| title_full_unstemmed | Role of the Skin Microenvironment in Melanomagenesis: Epidermal Keratinocytes and Dermal Fibroblasts Promote BRAF Oncogene-Induced Senescence Escape in Melanocytes |
| title_short | Role of the Skin Microenvironment in Melanomagenesis: Epidermal Keratinocytes and Dermal Fibroblasts Promote BRAF Oncogene-Induced Senescence Escape in Melanocytes |
| title_sort | role of the skin microenvironment in melanomagenesis epidermal keratinocytes and dermal fibroblasts promote braf oncogene induced senescence escape in melanocytes |
| topic | melanoma tumor microenvironment senescence microfluidics |
| url | https://www.mdpi.com/2072-6694/14/5/1233 |
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