Neural Crest-Like Stem Cell Transcriptome Analysis Identifies LPAR1 in Melanoma Progression and Therapy Resistance

Jianglan Liu, Vito W. Rebecca, Andrew V. Kossenkov, Thomas Connelly, Qin Liu, Alexis Gutierrez, Min Xiao, Ling Li, Gao Zhang, Anastasia Samarkina, Delaine Zayasbazan, Jie Zhang, Chaoran Cheng, Zhi Wei, Gretchen M. Alicea, Mizuho Fukunaga-Kalabis, Clemens Krepler, Pedro Aza-Blanc, Chih Cheng Yang, Bela DelvadiaCynthia Tong, Ye Huang, Maya Delvadia, Alice S. Morias, Katrin Sproesser, Patricia Brafford, Joshua X. Wang, Marilda Beqiri, Rajasekharan Somasundaram, Adina Vultur, Denitsa M. Hristova, Lawrence W. Wu, Yiling Lu, Gordon B. Mills, Wei Xu, Giorgos C. Karakousis, Xiaowei Xu, Lynn M. Schuchter, Tara C. Mitchell, Ravi K. Amaravadi, Lawrence N. Kwong, Dennie T. Frederick, Genevieve M. Boland, Joseph M. Salvino, David W. Speicher, Keith T. Flaherty, Ze'ev A. Ronai, Meenhard Herlyn

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)5230-5241
Number of pages12
JournalCancer Research
Volume81
Issue number20
DOIs
StatePublished - Oct 15 2021

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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