Johns Eleanor, Ma Yilun, Louphrasitthipol Pakavarin, Peralta Christopher, Hunter Miranda V, Raymond Jeremy H, Molina Henrik, Goding Colin R, White Richard M
bioRxiv. 2024 Mar 28:2024.03.25.586589. doi: 10.1101/2024.03.25.586589.
Lipid droplets are fat storage organelles composed of a protein envelope and lipid rich core. Regulation of this protein envelope underlies differential lipid droplet formation and function. In melanoma, lipid droplet formation has been linked to tumor progression and metastasis, but it is unknown whether lipid droplet proteins play a role. To address this, we performed proteomic analysis of the lipid droplet envelope in melanoma. We found that lipid droplet proteins were differentially enriched in distinct melanoma states; from melanocytic to undifferentiated. DHRS3, which converts all-trans-retinal to all-trans-retinol, is upregulated in the MITFLO/undifferentiated/neural crest-like melanoma cell state and reduced in the MITFHI/melanocytic state. Increased DHRS3 expression is sufficient to drive MITFHI/melanocytic cells to a more undifferentiated/invasive state. These changes are due to retinoic acid mediated regulation of melanocytic genes. Our data demonstrate that melanoma cell state can be regulated by expression of lipid droplet proteins which affect downstream retinoid signaling.
脂滴是由蛋白质包膜和富含脂质的核心组成的脂肪储存细胞器。这种蛋白质包膜的调节是脂滴形成和功能差异的基础。在黑色素瘤中，脂滴的形成与肿瘤进展和转移有关，但脂滴蛋白是否发挥作用尚不清楚。为了解决这个问题，我们对黑色素瘤中的脂滴包膜进行了蛋白质组学分析。我们发现脂滴蛋白在不同的黑色素瘤状态中差异富集；从黑素细胞状态到未分化状态。将全反式视黄醛转化为全反式视黄醇的DHRS3在MITFLO/未分化/神经嵴样黑色素瘤细胞状态中上调，而在MITFHI/黑素细胞状态中下调。DHRS3表达的增加足以驱使MITFHI/黑素细胞进入更未分化/侵袭性的状态。这些变化是由于视黄酸介导的黑素细胞基因调节。我们的数据表明，黑色素瘤细胞状态可以通过影响下游类视黄醇信号传导的脂滴蛋白的表达来调节。
