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Updated: Oct 22, 2025
Patient Derived Cell Culture and Isolation of CD133+ Putative Cancer Stem Cells from Melanoma
Published on: March 13, 2013
Neural Crest-Like Stem Cell Transcriptome Analysis Identifies LPAR1 in Melanoma Progression and Therapy Resistance
Jianglan Liu1, Vito W Rebecca1,2, Andrew V Kossenkov1
1Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania.
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.
Insights
Researchers identified a developmental LPAR1-axis crucial for neural crest-like stem cell (NCLSC) survival and melanoma cell resistance. Inhibiting LPAR1 enhanced targeted therapy efficacy and reduced melanoma invasion, revealing LPAR1 as a potential therapeutic target.
Area of Science:
- Oncology
- Developmental Biology
- Cell Biology
Background:
- Metastatic melanoma presents significant clinical challenges, with frequent relapse despite targeted therapies for BRAF-mutant cases.
- Intrinsically resistant melanoma cells exhibit properties of neural crest-like stem cells (NCLSCs), including invasiveness and self-renewal, contributing to therapeutic resistance.
Purpose of the Study:
- To investigate shared transcriptional programs and vulnerabilities between NCLSCs and melanoma cells.
- To identify novel therapeutic targets for overcoming melanoma resistance.
Main Methods:
- Identification of a developmental LPAR1-axis.
- Assessment of LPAR1 activity during melanoma progression and therapeutic resistance.
- Genetic inhibition of LPAR1 to evaluate its impact on BRAFi ± MEKi efficacy, melanoma migration, and invasion.
Main Results:
- A critical LPAR1-axis essential for NCLSC and melanoma cell survival was identified.
- LPAR1 activity was found to increase with melanoma progression and acquired therapeutic resistance.
- Genetic LPAR1 inhibition potentiated BRAFi ± MEKi efficacy and significantly reduced melanoma cell migration and invasion.
Conclusions:
- LPAR1 is a novel therapeutic target for melanoma treatment.
- Dissecting stem cell-like pathways, such as the LPAR1-axis, offers promise for overcoming melanoma therapy resistance and invasion.
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