| Literature DB >> 34462276 |
Jianglan Liu1, Vito W Rebecca1,2, Andrew V Kossenkov1, Thomas Connelly1, Qin Liu1, Alexis Gutierrez1, Min Xiao1, Ling Li1, Gao Zhang1, Anastasia Samarkina1, Delaine Zayasbazan1, Jie Zhang3, Chaoran Cheng3, Zhi Wei3, Gretchen M Alicea1, Mizuho Fukunaga-Kalabis1, Clemens Krepler1, Pedro Aza-Blanc4, Chih-Cheng Yang4, Bela Delvadia1, Cynthia Tong1, Ye Huang1, Maya Delvadia1, Alice S Morias1, Katrin Sproesser1, Patricia Brafford1, Joshua X Wang1, Marilda Beqiri1, Rajasekharan Somasundaram1, Adina Vultur1, Denitsa M Hristova1, Lawrence W Wu1, Yiling Lu5, Gordon B Mills5, Wei Xu6, Giorgos C Karakousis7, Xiaowei Xu8, Lynn M Schuchter6, Tara C Mitchell6, Ravi K Amaravadi6, Lawrence N Kwong9, Dennie T Frederick10, Genevieve M Boland10, Joseph M Salvino1, David W Speicher1, Keith T Flaherty11,12, Ze'ev A Ronai4, Meenhard Herlyn13.
Abstract
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. ©2021 The Authors; Published by the American Association for Cancer Research.Entities:
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Year: 2021 PMID： 34462276 PMCID： PMC8530965 DOI： 10.1158/0008-5472.CAN-20-1496
Source DB: PubMed Journal: Cancer Res ISSN： 0008-5472 Impact factor: 13.312