Sadangi Shreyans, Milosavljevic Katarina, Castro-Perez Edgardo, Lares Marcos, Singh Mithalesh, Altameemi Sarah, Beebe David J, Ayuso Jose M, Setaluri Vijayasaradhi
Department of Dermatology, University of Wisconsin-Madison, Madison, WI 53705, USA.
Department of Pathology and Laboratory Medicine, University of Wisconsin, 1111 Highland Ave., Madison, WI 53705, USA.
Cancers (Basel). 2022 Feb 27;14(5):1233. doi: 10.3390/cancers14051233.
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 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 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.
是黑色素瘤中最常见的突变驱动因素。已知这种突变会导致短暂的增殖爆发，随后是生长停滞和衰老，从而防止细胞不受控制地增殖。这种现象被称为癌基因诱导的衰老（OIS），并且OIS逃逸被认为会导致黑色素瘤的发生。许多注意力都集中在导致衰老逃逸的黑色素细胞内在机制上。已经描述了其他遗传事件，如肿瘤抑制因子的缺失和/或导致衰老逃逸的表观遗传变化。然而，皮肤微环境的作用，特别是表皮角质形成细胞在黑色素瘤发生中的作用尚未完全了解。在这项研究中，我们采用微流控平台来研究表达该突变的黑色素细胞与角质形成细胞和真皮成纤维细胞之间的相互作用。我们证明角质形成细胞抑制衰老相关基因并促进转化的黑色素细胞的增殖。我们还表明，角质形成细胞条件培养基可以改变转化的黑色素细胞分泌促肿瘤和抗肿瘤因子。此外，我们表明来自欧洲白人和非洲黑人供体的黑色素细胞和角质形成细胞表现出不同的相互作用；即，与黑色角质形成细胞相比，白色角质形成细胞似乎促进了更具促肿瘤性的表型。这些数据表明，角质形成细胞通过抑制黑色素细胞中与衰老相关的基因以及影响有利于肿瘤发生的黑色素细胞分泌因子的平衡，对黑色素瘤的发生产生影响。
