Metastatic melanoma is challenging to clinically address. Although standard-of-care targeted therapy has high response rates in patients with BRAF-mutant melanoma, therapy relapse occurs in most cases. Intrinsically resistant melanoma cells drive therapy resistance and display molecular and biologic properties akin to neural crest-like stem cells (NCLSC) including high invasiveness, plasticity, and self-renewal capacity. The shared transcriptional programs and vulnerabilities between NCLSCs and cancer cells remains poorly understood. Here, we identify a developmental LPAR1-axis critical for NCLSC viability and melanoma cell survival. LPAR1 activity increased during progression and following acquisition of therapeutic resistance. Notably, genetic inhibition of LPAR1 potentiated BRAFi ± MEKi efficacy and ablated melanoma migration and invasion. Our data define LPAR1 as a new therapeutic target in melanoma and highlights the promise of dissecting stem cell–like pathways hijacked by tumor cells. Significance: This study identifies an LPAR1-axis critical for melanoma invasion and intrinsic/acquired therapy resistance.

中文翻译：

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神经嵴样干细胞转录组分析鉴定黑色素瘤进展和治疗耐药性中的 LPAR1

转移性黑色素瘤在临床上具有挑战性。尽管标准护理靶向治疗对 BRAF 突变黑色素瘤患者有很高的反应率，但在大多数情况下会发生治疗复发。内在耐药的黑色素瘤细胞驱动治疗耐药并显示出类似于神经嵴样干细胞 (NCLSC) 的分子和生物学特性，包括高侵袭性、可塑性和自我更新能力。NCLSC 和癌细胞之间共享的转录程序和弱点仍然知之甚少。在这里，我们确定了对 NCLSC 活力和黑色素瘤细胞存活至关重要的发育 LPAR1 轴。LPAR1 活性在进展期间和获得治疗抗性后增加。值得注意的是，LPAR1 的基因抑制增强了 BRAFi ± MEKi 功效并消除了黑色素瘤的迁移和侵袭。我们的数据将 LPAR1 定义为黑色素瘤的新治疗靶点，并强调了剖析被肿瘤细胞劫持的干细胞样通路的前景。意义：本研究确定了对黑色素瘤侵袭和内在/获得性治疗耐药性至关重要的 LPAR1 轴。