Rasmussen Martin Q, Bønnelykke-Behrndtz Marie L, Merrild Camilla, Tvilling Ida, Christensen Julie N, Nielsen Morten M, Georgsen Jeanette B, Naumann Nina, Gudbergsson Johann M, Etzerodt Anders, Pedersen Jakob S, Jenkins Russell W, Degn Søren E, Moestrup Søren K, Schmidt Henrik, Steiniche Torben, Madsen Mette
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Department of Plastic- and Breast Surgery, Aarhus University Hospital, Aarhus, Denmark.
Pigment Cell Melanoma Res. 2025 Sep;38(5):e70053. doi: 10.1111/pcmr.70053.
Low density lipoprotein receptor-related protein 2 (LRP2) is a 600 kilodalton multi-ligand endocytic membrane receptor expressed in several cell types during fetal development, including neuroepithelial cells, and in select absorptive epithelial cells in the adult. In epithelial cancers, LRP2 expression is associated with a differentiated tumor cell state and better prognosis. In previous work, we found that while LRP2 is not expressed in benign naevi, it is frequently acquired in melanoma. However, the molecular drivers of LRP2 expression in melanoma and characteristics of LRP2-expressing melanoma have yet to be described. Here, we show that LRP2 expression is related to a transitory melanoma cell state defined by co-expression of melanocyte lineage and neural crest transcriptional programs. Further, we reveal that melanoma LRP2 expression is increased in T cell-inflamed tumors and is directly upregulated through interferon-gamma signaling. Correlation of melanoma LRP2 expression with clinicopathological variables demonstrates that LRP2 expression is associated with low Breslow thickness and low clinical stage in primary melanomas. Taken together, the present study describes the characteristics of LRP2-expressing melanoma and reveals interferon-gamma signaling as a novel strong positive regulator of LRP2 expression in melanoma.
低密度脂蛋白受体相关蛋白2（LRP2）是一种600千道尔顿的多配体内吞膜受体，在胎儿发育期间于多种细胞类型中表达，包括神经上皮细胞，在成体中则表达于特定的吸收性上皮细胞。在上皮性癌中，LRP2表达与肿瘤细胞的分化状态及较好的预后相关。在先前的研究中，我们发现LRP2在良性痣中不表达，但在黑色素瘤中经常获得表达。然而，黑色素瘤中LRP2表达的分子驱动因素以及表达LRP2的黑色素瘤的特征尚未见报道。在此，我们表明LRP2表达与一种由黑素细胞谱系和神经嵴转录程序共表达所定义的短暂性黑色素瘤细胞状态相关。此外，我们揭示黑色素瘤LRP2表达在T细胞炎症性肿瘤中增加，并且通过γ干扰素信号直接上调。黑色素瘤LRP2表达与临床病理变量的相关性表明，LRP2表达与原发性黑色素瘤的低Breslow厚度和低临床分期相关。综上所述，本研究描述了表达LRP2的黑色素瘤的特征，并揭示γ干扰素信号是黑色素瘤中LRP2表达的一种新的强阳性调节因子。
