1. Neural Crest-Like Stem Cell Transcriptome Analysis Identifies LPAR1 in Melanoma Progression and Therapy Resistance.
- Author
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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, and Herlyn M
- Subjects
- Animals, Antineoplastic Agents pharmacology, Apoptosis, Biomarkers, Tumor genetics, Cell Proliferation, Humans, Melanoma drug therapy, Melanoma genetics, Melanoma metabolism, Mice, Mice, Inbred NOD, Mice, SCID, Neural Crest drug effects, Neural Crest metabolism, Neural Stem Cells drug effects, Neural Stem Cells metabolism, Prognosis, Receptors, Lysophosphatidic Acid genetics, Transcriptome, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Biomarkers, Tumor metabolism, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Melanoma pathology, Neural Crest pathology, Neural Stem Cells pathology, Receptors, Lysophosphatidic Acid metabolism
- 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.)
- Published
- 2021
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