Neural Crest-Like Stem Cell Transcriptome Analysis Identifies LPAR1 in Melanoma Progression and Therapy Resistance.
Neural Crest-Like Stem Cell Transcriptome Analysis Identifies LPAR1 in Melanoma Progression and Therapy Resistance.
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DOI：
10.1158/0008-5472.can-20-1496
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发表时间：
2021-10-15
期刊：
影响因子：
11.2
通讯作者：
Herlyn M
中科院分区：
文献类型：
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作者：
Liu J;Rebecca VW;Kossenkov AV;Connelly T;Liu Q;Gutierrez A;Xiao M;Li L;Zhang G;Samarkina A;Zayasbazan D;Zhang J;Cheng C;Wei Z;Alicea GM;Fukunaga-Kalabis M;Krepler C;Aza-Blanc P;Yang CC;Delvadia B;Tong C;Huang Y;Delvadia M;Morias AS;Sproesser K;Brafford P;Wang JX;Beqiri M;Somasundaram R;Vultur A;Hristova DM;Wu LW;Lu Y;Mills GB;Xu W;Karakousis GC;Xu X;Schuchter LM;Mitchell TC;Amaravadi RK;Kwong LN;Frederick DT;Boland GM;Salvino JM;Speicher DW;Flaherty KT;Ronai ZA;Herlyn M
这项研究确定了 LPAR1 轴对于黑色素瘤侵袭和内在/获得性治疗耐药至关重要。转移性黑色素瘤在临床上很难解决。尽管标准护理靶向治疗对 BRAF 突变黑色素瘤患者有较高的缓解率，但大多数情况下会出现治疗复发。内在耐药的黑色素瘤细胞会导致治疗耐药，并表现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脆弱性仍然知之甚少。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 活性在进展过程中和获得治疗耐药性后增加。值得注意的是，LPAR1 的基因抑制增强了 BRAFi ± MEKi 的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。这项研究确定了 LPAR1 轴对于黑色素瘤侵袭和内在/获得性治疗耐药至关重要。
This study identifies an LPAR1-axis critical for melanoma invasion and intrinsic/acquired therapy resistance. 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. This study identifies an LPAR1-axis critical for melanoma invasion and intrinsic/acquired therapy resistance.