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 Delvadia; Cynthia 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

doi:10.1158/0008-5472.CAN-20-1496

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 journal › Article › peer-review

11 Scopus citations

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 language	English (US)
Pages (from-to)	5230-5241
Number of pages	12
Journal	Cancer Research
Volume	81
Issue number	20
DOIs	https://doi.org/10.1158/0008-5472.CAN-20-1496
State	Published - Oct 15 2021
Externally published	Yes

All Science Journal Classification (ASJC) codes

Oncology
Cancer Research

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10.1158/0008-5472.CAN-20-1496

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Liu, J., Rebecca, V. W., Kossenkov, A. V., Connelly, T., Liu, Q., Gutierrez, A., Xiao, M., Li, L., Zhang, G., Samarkina, A., Zayasbazan, D., Zhang, J., Cheng, C., Wei, Z., Alicea, G. M., Fukunaga-Kalabis, M., Krepler, C., Aza-Blanc, P., Yang, C. C., ... Herlyn, M. (2021). Neural Crest-Like Stem Cell Transcriptome Analysis Identifies LPAR1 in Melanoma Progression and Therapy Resistance. Cancer Research, 81(20), 5230-5241. https://doi.org/10.1158/0008-5472.CAN-20-1496

@article{15a4386699cf46309e3864acd91bc38a,

title = "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.",

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

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = oct,

day = "15",

doi = "10.1158/0008-5472.CAN-20-1496",

language = "English (US)",

volume = "81",

pages = "5230--5241",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "20",

}

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 & Herlyn, M 2021, 'Neural Crest-Like Stem Cell Transcriptome Analysis Identifies LPAR1 in Melanoma Progression and Therapy Resistance', Cancer Research, vol. 81, no. 20, pp. 5230-5241. https://doi.org/10.1158/0008-5472.CAN-20-1496

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

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.

UR - http://www.scopus.com/inward/record.url?scp=85117719587&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85117719587&partnerID=8YFLogxK

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 -

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

Abstract

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