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Melanoma mutations modify melanocyte dynamics in co-culture with keratinocytes or fibroblasts.
Journal of Cell Science ( IF 3.3 ) Pub Date : 2019-12-13 , DOI: 10.1242/jcs.234716
Dubravka Škalamera 1 , Alexander J Stevenson 2 , Anna Ehmann 2 , Stephen A Ainger 3 , Catherine Lanagan 2 , Richard A Sturm 3 , Brian Gabrielli 2
Affiliation  

Melanocytic cell interactions are integral to skin homeostasis, and affect the outcome of multiple diseases, including cutaneous pigmentation disorders and melanoma. By using automated-microscopy and machine-learning-assisted morphology analysis of primary human melanocytes in co-culture, we performed combinatorial interrogation of melanocyte genotypic variants and functional assessment of lentivirus-introduced mutations. Keratinocyte-induced melanocyte dendricity, an indicator of melanocyte differentiation, was reduced in the melanocortin 1 receptor (MC1R) R/R variant strain and by NRAS.Q61K and BRAF.V600E expression, while expression of CDK4.R24C and RAC1.P29S had no detectable effect. Time-lapse tracking of melanocytes in co-culture revealed dynamic interaction phenotypes and hyper-motile cell states that indicated that, in addition to the known role in activating mitogenic signalling, MEK-pathway-activating mutations may also allow melanocytes to escape keratinocyte control and increase their invasive potential. Expanding this combinatorial platform will identify other therapeutic target mutations and melanocyte genetic variants, as well as increase understanding of skin cell interactions.

中文翻译:

黑色素瘤突变可在与角质形成细胞或成纤维细胞共培养时改变黑色素细胞的动力学。

黑素细胞相互作用是皮肤稳态所不可或缺的,并影响多种疾病的结果,包括皮肤色素沉着症和黑色素瘤。通过使用自动显微镜和机器学习辅助的共培养中人类黑素细胞的形态分析,我们进行了黑素细胞基因型变异的组合询问和慢病毒引入突变的功能评估。黑素皮质素1受体(MC1R)R / R变异株和NRAS.Q61K和BRAF.V600E的表达降低了角质形成细胞诱导的黑素细胞树突,这是黑素细胞分化的指标,而CDK4.R24C和RAC1.P29S的表达则没有可检测的效果。在共培养中对黑素细胞的时移跟踪揭示了动态相互作用表型和能动性较高的细胞状态,表明:除了在激活有丝分裂信号中的已知作用外,MEK途径激活突变还可能使黑素细胞逃脱角质形成细胞的控制并增加其侵袭潜力。扩展该组合平台将确定其他治疗靶点突变和黑素细胞遗传变异,并增加对皮肤细胞相互作用的了解。
更新日期:2019-12-30
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