TY - JOUR
T1 - Targeting SOX10-deficient cells to reduce the dormant-invasive phenotype state in melanoma
AU - Capparelli, Claudia
AU - Purwin, Timothy J.
AU - Glasheen, McKenna K.
AU - Caksa, Signe
AU - Tiago, Manoela
AU - Wilski, Nicole
AU - Pomante, Danielle
AU - Rosenbaum, Sheera
AU - Nguyen, Mai Q.
AU - Cai, Weijia
AU - Franco-Barraza, Janusz
AU - Zheng, Richard
AU - Kumar, Gaurav
AU - Chervoneva, Inna
AU - Shimada, Ayako
AU - Rebecca, Vito W.
AU - Snook, Adam E.
AU - Hookim, Kim
AU - Xu, Xiaowei
AU - Cukierman, Edna
AU - Herlyn, Meenhard
AU - Aplin, Andrew E.
N1 - Funding Information:
A.E.A. reports receiving a commercial research grant from Pfizer Inc. (2013-2017) and has ownership interest in patent number 9880150. E.C. wishes to disclose that she is currently a consultant and SAB member for Phenomic AI. X.X. is the co-founder and shareholder of CureBiotech, Inc, and Exio Bioscience and he also did consultant work for BMS. The remaining authors declare no competing interests.
Funding Information:
This work was supported by grants from American Cancer Society (130042-IRG-16-244-10-IRG), Melanoma Research Foundation and Legacy of Hope Merit Award to C.C. M.H. and A.E.A. were both supported by P01 CA114046-11A1. Additional support was provided by NIH/NCI R01 (CA196278), Department of Defense (CA171056), and Dr. Miriam and Sheldon G. Adelson Medical Research Foundation awards to A.E.A. Additionally, the Melanoma Research Alliance Award #568992 to Drs Melissa Wilson and Andrew Aplin. The Sidney Kimmel Cancer Center Flow Cytometry, Meta-Omics, Translational Pathology, Laboratory Animal and Bio-Imaging core facilities are supported by National Cancer Center Support Grant (P30 CA056036). Support for the Molecular Screening Facility at The Wistar Institute was provided by Cancer Center Support Grant, CA010815. Additional support was provided by NIH/NCI (R01 CA232256) to E.C. The Fox Chase Cancer Center Microscopy/Imaging, Immune Monitoring, Cell Culturing, and Histochemistry facilities used in this study are supported by the Comprehensive Cancer Center Grant NCI (P30 CA06927) and NIH/NCI grant (S10ODO23666). We thank the National Cancer Institute ("NCI") Division of Cancer Treatments and Diagnosis (DCTD) for providing birinapant for in vivo studies. We are grateful to Dr. Barbara Bedogni (University of Miami) and Dr. David Solit (Memorial Sloan-Kettering Cancer Center) for generously providing cell lines. We are grateful to Joel Cassel (The Wistar Institute) for performing the drug screen using an anti-cancer library compound panel and to Dr. Gideon Bollag (Plexxikon Inc., Berkeley CA) for providing PLX4720, PLX2695/PD'901, and PLX8394. We thank Dr. Edward Hartsough (Drexel University) for generating the 1205Lu and PBRTs samples for RNA-seq. At Thomas Jefferson University, we thank Dr. Timothy L. Manser and Trevor Baybutt for the NSG mice colonies, Dr. Paolo Fortina and Dr. Adam Ertel for their help with computational analysis, Dr. Maria Yolanda Covarrubias for her help with confocal microscopy, Dr. Zhijiu Zhong and Raymond O'Neill for helping with immune-histochemistry, and Dr. Lei Yu and Amir Yarmahmoodi for cell sorting. We also acknowledge Dr. Ed Hartsough for generating the PBRT cell lines and sending samples out for RNA-seq.
Funding Information:
This work was supported by grants from American Cancer Society (130042-IRG-16-244-10-IRG), Melanoma Research Foundation and Legacy of Hope Merit Award to C.C. M.H. and A.E.A. were both supported by P01 CA114046-11A1. Additional support was provided by NIH/NCI R01 (CA196278), Department of Defense (CA171056), and Dr. Miriam and Sheldon G. Adelson Medical Research Foundation awards to A.E.A. Additionally, the Melanoma Research Alliance Award #568992 to Drs Melissa Wilson and Andrew Aplin. The Sidney Kimmel Cancer Center Flow Cytometry, Meta-Omics, Translational Pathology, Laboratory Animal and Bio-Imaging core facilities are supported by National Cancer Center Support Grant (P30 CA056036). Support for the Molecular Screening Facility at The Wistar Institute was provided by Cancer Center Support Grant, CA010815. Additional support was provided by NIH/NCI (R01 CA232256) to E.C. The Fox Chase Cancer Center Microscopy/Imaging, Immune Monitoring, Cell Culturing, and Histochemistry facilities used in this study are supported by the Comprehensive Cancer Center Grant NCI (P30 CA06927) and NIH/NCI grant (S10ODO23666). We thank the National Cancer Institute ("NCI") Division of Cancer Treatments and Diagnosis (DCTD) for providing birinapant for in vivo studies. We are grateful to Dr. Barbara Bedogni (University of Miami) and Dr. David Solit (Memorial Sloan-Kettering Cancer Center) for generously providing cell lines. We are grateful to Joel Cassel (The Wistar Institute) for performing the drug screen using an anti-cancer library compound panel and to Dr. Gideon Bollag (Plexxikon Inc., Berkeley CA) for providing PLX4720, PLX2695/PD'901, and PLX8394. We thank Dr. Edward Hartsough (Drexel University) for generating the 1205Lu and PBRTs samples for RNA-seq. At Thomas Jefferson University, we thank Dr. Timothy L. Manser and Trevor Baybutt for the NSG mice colonies, Dr. Paolo Fortina and Dr. Adam Ertel for their help with computational analysis, Dr. Maria Yolanda Covarrubias for her help with confocal microscopy, Dr. Zhijiu Zhong and Raymond O'Neill for helping with immune-histochemistry, and Dr. Lei Yu and Amir Yarmahmoodi for cell sorting. We also acknowledge Dr. Ed Hartsough for generating the PBRT cell lines and sending samples out for RNA-seq.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Cellular plasticity contributes to intra-tumoral heterogeneity and phenotype switching, which enable adaptation to metastatic microenvironments and resistance to therapies. Mechanisms underlying tumor cell plasticity remain poorly understood. SOX10, a neural crest lineage transcription factor, is heterogeneously expressed in melanomas. Loss of SOX10 reduces proliferation, leads to invasive properties, including the expression of mesenchymal genes and extracellular matrix, and promotes tolerance to BRAF and/or MEK inhibitors. We identify the class of cellular inhibitor of apoptosis protein-1/2 (cIAP1/2) inhibitors as inducing cell death selectively in SOX10-deficient cells. Targeted therapy selects for SOX10 knockout cells underscoring their drug tolerant properties. Combining cIAP1/2 inhibitor with BRAF/MEK inhibitors delays the onset of acquired resistance in melanomas in vivo. These data suggest that SOX10 mediates phenotypic switching in cutaneous melanoma to produce a targeted inhibitor tolerant state that is likely a prelude to the acquisition of resistance. Furthermore, we provide a therapeutic strategy to selectively eliminate SOX10-deficient cells.
AB - Cellular plasticity contributes to intra-tumoral heterogeneity and phenotype switching, which enable adaptation to metastatic microenvironments and resistance to therapies. Mechanisms underlying tumor cell plasticity remain poorly understood. SOX10, a neural crest lineage transcription factor, is heterogeneously expressed in melanomas. Loss of SOX10 reduces proliferation, leads to invasive properties, including the expression of mesenchymal genes and extracellular matrix, and promotes tolerance to BRAF and/or MEK inhibitors. We identify the class of cellular inhibitor of apoptosis protein-1/2 (cIAP1/2) inhibitors as inducing cell death selectively in SOX10-deficient cells. Targeted therapy selects for SOX10 knockout cells underscoring their drug tolerant properties. Combining cIAP1/2 inhibitor with BRAF/MEK inhibitors delays the onset of acquired resistance in melanomas in vivo. These data suggest that SOX10 mediates phenotypic switching in cutaneous melanoma to produce a targeted inhibitor tolerant state that is likely a prelude to the acquisition of resistance. Furthermore, we provide a therapeutic strategy to selectively eliminate SOX10-deficient cells.
UR - http://www.scopus.com/inward/record.url?scp=85126725606&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85126725606&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-28801-y
DO - 10.1038/s41467-022-28801-y
M3 - Article
C2 - 35296667
AN - SCOPUS:85126725606
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1381
ER -