黑色素瘤是一种高度恶性肿瘤，是最致命的皮肤癌，具有显着的表型可塑性和瘤内异质性。黑色素瘤的可塑性与肿瘤生长、转移和治疗抵抗有关。长非编码 RNA (lncRNA) 由于其调节功能可能会影响可塑性。然而，它们的作用和作用方式却很少被研究。在这里，我们展示了 lncRNA GRASLND 在黑色素瘤分化和 IFNγ 信号传导中的相关性。 GRASLND 敲低揭示了分化的黑素细胞黑色素瘤细胞向去分化、缓慢增殖和高侵袭性细胞状态的转变。有趣的是，GRASLND 在分化的黑色素瘤中过度表达，并与不良预后相关。因此，我们发现 GRASLND 在免疫“冷”肿瘤中表达，并且与免疫反应激活的基因特征负相关。与此一致，在 IFNγ 下沉默 GRASLND 增强了 IFNγ 刺激基因的表达，包括 HLA-I 抗原呈递，证明了 GRASLND 对 IFNγ 信号传导的抑制活性。我们的研究结果表明，在分化的黑色素瘤中，GRASLND 的表达升高会干扰 IFNγ 的抗肿瘤作用，表明 GRASLND 在肿瘤免疫逃避中发挥作用。版权所有 © 2024 Fischer、Tiwari、Thier、Qiu、Lin、Paschen 和 Imig。

Melanoma is a highly malignant tumor, that stands as the most lethal form of skin cancer and is characterized by notable phenotypic plasticity and intratumoral heterogeneity. Melanoma plasticity is involved in tumor growth, metastasis and therapy resistance. Long non-coding RNAs (lncRNAs) could influence plasticity due to their regulatory function. However, their role and mode of action are poorly studied. Here, we show a relevance of lncRNA GRASLND in melanoma differentiation and IFNγ signaling. GRASLND knockdown revealed switching of differentiated, melanocytic melanoma cells towards a dedifferentiated, slow-proliferating and highly-invasive cell state. Interestingly, GRASLND is overexpressed in differentiated melanomas and associated with poor prognosis. Accordingly, we found GRASLND expressed in immunological "cold" tumors and it negatively correlates with gene signatures of immune response activation. In line, silencing of GRASLND under IFNγ enhanced the expression of IFNγ-stimulated genes, including HLA-I antigen presentation, demonstrating suppressive activity of GRASLND on IFNγ signaling. Our findings demonstrate that in differentiated melanomas elevated expression of GRASLND interferes with anti-tumor effects of IFNγ, suggesting a role of GRASLND in tumor immune evasion.Copyright © 2024 Fischer, Tiwari, Thier, Qiu, Lin, Paschen and Imig.