TY - JOUR
T1 - Neural Crest-Like Stem Cell Transcriptome Analysis Identifies LPAR1 in Melanoma Progression and Therapy Resistance
AU - Liu, Jianglan
AU - Rebecca, Vito W.
AU - Kossenkov, Andrew V.
AU - Connelly, Thomas
AU - Liu, Qin
AU - Gutierrez, Alexis
AU - Xiao, Min
AU - Li, Ling
AU - Zhang, Gao
AU - Samarkina, Anastasia
AU - Zayasbazan, Delaine
AU - Zhang, Jie
AU - Cheng, Chaoran
AU - Wei, Zhi
AU - Alicea, Gretchen M.
AU - Fukunaga-Kalabis, Mizuho
AU - Krepler, Clemens
AU - Aza-Blanc, Pedro
AU - Yang, Chih Cheng
AU - Delvadia, Bela
AU - Tong, Cynthia
AU - Huang, Ye
AU - Delvadia, Maya
AU - Morias, Alice S.
AU - Sproesser, Katrin
AU - Brafford, Patricia
AU - Wang, Joshua X.
AU - Beqiri, Marilda
AU - Somasundaram, Rajasekharan
AU - Vultur, Adina
AU - Hristova, Denitsa M.
AU - Wu, Lawrence W.
AU - Lu, Yiling
AU - Mills, Gordon B.
AU - Xu, Wei
AU - Karakousis, Giorgos C.
AU - Xu, Xiaowei
AU - Schuchter, Lynn M.
AU - Mitchell, Tara C.
AU - Amaravadi, Ravi K.
AU - Kwong, Lawrence N.
AU - Frederick, Dennie T.
AU - Boland, Genevieve M.
AU - Salvino, Joseph M.
AU - Speicher, David W.
AU - Flaherty, Keith T.
AU - Ronai, Ze'ev A.
AU - Herlyn, Meenhard
N1 - Funding Information:
Foundation, and the Melanoma Research Foundation. The support for Shared Resources utilized in this study was provided by Cancer Center Support Grant (CCSG) CA010815 and S10 OD023586 to the Wistar Institute.
Funding Information:
The authors thank all former and current lab members for comments and helpful discussions; J. Hayden and F. Keeney (Wistar Microscopy Facility), C. Chang, S. Billouin, and T. Nguyen (Wistar Genomics Facility), and J.S. Faust and D. Ambrose (Wistar Flow Cytometry Facility) for technical support. The authors apologize to those whose work was not cited or mentioned here due to space constraints. The research was supported by NIH grants R01 CA 182890, U54 CA224070, P01 CA114046, P01 CA025874, P30 CA010815, R01 CA047159, K01 CA245124, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the Melanoma Research Foundation. The support for Shared Resources utilized in this study was provided by Cancer Center Support Grant (CCSG) CA010815 and S10 OD023586 to the Wistar Institute.
Funding Information:
The authors thank all former and current lab members for comments and helpful discussions; J. Hayden and F. Keeney (Wistar Microscopy Facility), C. Chang, S. Billouin, and T. Nguyen (Wistar Genomics Facility), and J.S. Faust and D. Ambrose (Wistar Flow Cytometry Facility) for technical support. The authors apologize to those whose work was not cited or mentioned here due to space constraints. The research was supported by NIH grants R01 CA 182890, U54 CA224070, P01 CA114046, P01 CA025874, P30 CA010815, R01 CA047159, K01 CA245124, the Dr. Miriam and Sheldon G. Adelson Medical Research
Publisher Copyright:
© 2021 The Authors
PY - 2021/10/15
Y1 - 2021/10/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-20-1496
DO - 10.1158/0008-5472.CAN-20-1496
M3 - Article
C2 - 34462276
AN - SCOPUS:85117719587
SN - 0008-5472
VL - 81
SP - 5230
EP - 5241
JO - Cancer Research
JF - Cancer Research
IS - 20
ER -