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

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.

SUBMITTER: Liu J

PROVIDER: S-EPMC8530965 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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

Liu Jianglan J Rebecca Vito W VW Kossenkov Andrew V AV Connelly Thomas T Liu Qin Q Gutierrez Alexis A Xiao Min M Li Ling L Zhang Gao G Samarkina Anastasia A Zayasbazan Delaine D Zhang Jie J Cheng Chaoran C Wei Zhi Z Alicea Gretchen M GM Fukunaga-Kalabis Mizuho M Krepler Clemens C Aza-Blanc Pedro P Yang Chih-Cheng CC Delvadia Bela B Tong Cynthia C Huang Ye Y Delvadia Maya M Morias Alice S AS Sproesser Katrin K Brafford Patricia P Wang Joshua X JX Beqiri Marilda M Somasundaram Rajasekharan R Vultur Adina A Hristova Denitsa M DM Wu Lawrence W LW Lu Yiling Y Mills Gordon B GB Xu Wei W Karakousis Giorgos C GC Xu Xiaowei X Schuchter Lynn M LM Mitchell Tara C TC Amaravadi Ravi K RK Kwong Lawrence N LN Frederick Dennie T DT Boland Genevieve M GM Salvino Joseph M JM Speicher David W DW Flaherty Keith T KT Ronai Ze'ev A ZA Herlyn Meenhard M

Cancer research 20210830 20

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 ...[more]

PMID: 34462276

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Project description:The identification of novel tumor-specific markers may improve understanding of melanoma progression and prognostic accuracy. Whole genome expression profiling of 46 primary melanomas, 12 metastases, and 16 normal skin samples using Affymetrix U133 PLUS 2.0 array generated gene lists including both known and new melanoma genes. The molecular genetic alterations contributing to the pathogenesis of melanoma are incompletely defined and few independent prognostic features have been identified beyond the pathologic characteristics of the primary tumor. Early stage melanoma is frequently curable, in contrast to the inferior prognosis of melanomas with regional lymph nodes involvement and the incurability of distant metastatic disease. The identification of novel tumor-specific markers may improve our understanding of melanoma progression and prognostic accuracy. To find differentially expressed genes that can distinguish melanoma from normal tissue, we performed a whole genome expression profiling of 46 primary melanoma samples, 12 regional or distant metastases, and 16 normal skin samples using Affymetrix U133 2.0 Plus array. Our study generated lists of differentially expressed genes in melanoma and identified novel prognostic marker HMGA2. It is a novel, highly overexpressed melanoma gene associated with poor prognosis. The overexpression of HMGA2 is strongly associated with regional and distant metastases and serves as an independent predictor of disease-free survival and overall survival in melanoma. Melanoma samples were obtained through an IRB-approved protocol using informed consent at the University of Michigan Multidisciplinary Melanoma Clinic. A portion of pigmented lesions clinically suspicious for melanoma and known melanoma were sampled by punch biopsy at the time of excision. The punch biopsy was bisected; half was sent to for clinical diagnosis and the other half along with adjacent normal skin when available immediately snap-frozen in liquid nitrogen. Snap-frozen tissue was embedded in OCT (TissueTek) followed by frozen sectioning and H&E slide preparation. The slides were evaluated by dermatopathologist who identified areas with greater than 70% tumor cellularity, which were sampled for RNA extraction. Primary melanomas and melanoma metastases were derived from different patients. Metastatic samples included lymph nodes (n=8), subcutaneous soft tissue (n=2), spleen (n=1), and small intestine (n=1).

Dataset Information

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

Publications

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

Similar Datasets

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