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A CTC-Cluster-Specific Signature Derived from OMICS Analysis of Patient-Derived Xenograft Tumors Predicts Outcomes in Basal-Like Breast Cancer

Circulating tumor cell clusters (CTCcl) have a higher metastatic potential compared to single CTCs and predict long-term outcomes in breast cancer (BC) patients. Because of the rarity of CTCcls, molecular characterization of primary tumors that give rise to CTCcl hold significant promise for better...

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Autores principales: Thangavel, Hariprasad, Angelis, Carmine De, Vasaikar, Suhas, Bhat, Raksha, Jolly, Mohit Kumar, Nagi, Chandandeep, Creighton, Chad J., Chen, Fengju, Dobrolecki, Lacey E., George, Jason T., Kumar, Tanya, Abdulkareem, Noor Mazin, Mao, Sufeng, Nardone, Agostina, Rimawi, Mothaffar, Osborne, C. Kent, Lewis, Michael T., Levine, Herbert, Zhang, Bing, Schiff, Rachel, Giuliano, Mario, Trivedi, Meghana V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912280/
https://www.ncbi.nlm.nih.gov/pubmed/31652963
http://dx.doi.org/10.3390/jcm8111772
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author Thangavel, Hariprasad
Angelis, Carmine De
Vasaikar, Suhas
Bhat, Raksha
Jolly, Mohit Kumar
Nagi, Chandandeep
Creighton, Chad J.
Chen, Fengju
Dobrolecki, Lacey E.
George, Jason T.
Kumar, Tanya
Abdulkareem, Noor Mazin
Mao, Sufeng
Nardone, Agostina
Rimawi, Mothaffar
Osborne, C. Kent
Lewis, Michael T.
Levine, Herbert
Zhang, Bing
Schiff, Rachel
Giuliano, Mario
Trivedi, Meghana V.
author_facet Thangavel, Hariprasad
Angelis, Carmine De
Vasaikar, Suhas
Bhat, Raksha
Jolly, Mohit Kumar
Nagi, Chandandeep
Creighton, Chad J.
Chen, Fengju
Dobrolecki, Lacey E.
George, Jason T.
Kumar, Tanya
Abdulkareem, Noor Mazin
Mao, Sufeng
Nardone, Agostina
Rimawi, Mothaffar
Osborne, C. Kent
Lewis, Michael T.
Levine, Herbert
Zhang, Bing
Schiff, Rachel
Giuliano, Mario
Trivedi, Meghana V.
author_sort Thangavel, Hariprasad
collection PubMed
description Circulating tumor cell clusters (CTCcl) have a higher metastatic potential compared to single CTCs and predict long-term outcomes in breast cancer (BC) patients. Because of the rarity of CTCcls, molecular characterization of primary tumors that give rise to CTCcl hold significant promise for better diagnosis and target discovery to combat metastatic BC. In our study, we utilized the reverse-phase protein array (RPPA) and transcriptomic (RNA-Seq) data of 10 triple-negative BC patient-derived xenograft (TNBC PDX) transplantable models with CTCs and evaluated expression of upregulated candidate protein Bcl2 (B-cell lymphoma 2) by immunohistochemistry (IHC). The sample-set consisted of six CTCcl-negative (CTCcl−) and four CTCcl-positive (CTCcl+) models. We analyzed the RPPA and transcriptomic profiles of CTCcl− and CTCcl+ TNBC PDX models. In addition, we derived a CTCcl-specific gene signature for testing if it predicted outcomes using a publicly available dataset from 360 patients with basal-like BC. The RPPA analysis of CTCcl+ vs. CTCcl− TNBC PDX tumors revealed elevated expression of Bcl2 (false discovery rate (FDR) < 0.0001, fold change (FC) = 3.5) and reduced acetyl coenzyme A carboxylase-1 (ACC1) (FDR = 0.0005, FC = 0.3) in CTCcl+ compared to CTCcl− tumors. Genome-wide transcriptomic analysis of CTCcl+ vs. CTCcl− tumors revealed 549 differentially expressed genes associated with the presence of CTCcls. Apoptosis was one of the significantly downregulated pathways (normalized enrichment score (NES) = −1.69; FDR < 0.05) in TNBC PDX tumors associated with CTCcl positivity. Two out of four CTCcl+ TNBC PDX primary tumors had high Bcl2 expression by IHC (H-score > 34); whereas, only one of six CTCcl− TNBC PDX primary tumors met this criterion. Evaluation of epithelial-mesenchymal transition (EMT)-specific signature did not show significant differences between CTCcl+ and CTCcl− tumors. However, a gene signature associated with the presence of CTCcls in TNBC PDX models was associated with worse relapse-free survival in the publicly available dataset from 360 patients with basal-like BC. In summary, we identified the multigene signature of primary PDX tumors associated with the presence of CTCcls. Evaluation of additional TNBC PDX models and patients can further illuminate cellular and molecular pathways facilitating CTCcl formation.
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spelling pubmed-69122802020-01-02 A CTC-Cluster-Specific Signature Derived from OMICS Analysis of Patient-Derived Xenograft Tumors Predicts Outcomes in Basal-Like Breast Cancer Thangavel, Hariprasad Angelis, Carmine De Vasaikar, Suhas Bhat, Raksha Jolly, Mohit Kumar Nagi, Chandandeep Creighton, Chad J. Chen, Fengju Dobrolecki, Lacey E. George, Jason T. Kumar, Tanya Abdulkareem, Noor Mazin Mao, Sufeng Nardone, Agostina Rimawi, Mothaffar Osborne, C. Kent Lewis, Michael T. Levine, Herbert Zhang, Bing Schiff, Rachel Giuliano, Mario Trivedi, Meghana V. J Clin Med Article Circulating tumor cell clusters (CTCcl) have a higher metastatic potential compared to single CTCs and predict long-term outcomes in breast cancer (BC) patients. Because of the rarity of CTCcls, molecular characterization of primary tumors that give rise to CTCcl hold significant promise for better diagnosis and target discovery to combat metastatic BC. In our study, we utilized the reverse-phase protein array (RPPA) and transcriptomic (RNA-Seq) data of 10 triple-negative BC patient-derived xenograft (TNBC PDX) transplantable models with CTCs and evaluated expression of upregulated candidate protein Bcl2 (B-cell lymphoma 2) by immunohistochemistry (IHC). The sample-set consisted of six CTCcl-negative (CTCcl−) and four CTCcl-positive (CTCcl+) models. We analyzed the RPPA and transcriptomic profiles of CTCcl− and CTCcl+ TNBC PDX models. In addition, we derived a CTCcl-specific gene signature for testing if it predicted outcomes using a publicly available dataset from 360 patients with basal-like BC. The RPPA analysis of CTCcl+ vs. CTCcl− TNBC PDX tumors revealed elevated expression of Bcl2 (false discovery rate (FDR) < 0.0001, fold change (FC) = 3.5) and reduced acetyl coenzyme A carboxylase-1 (ACC1) (FDR = 0.0005, FC = 0.3) in CTCcl+ compared to CTCcl− tumors. Genome-wide transcriptomic analysis of CTCcl+ vs. CTCcl− tumors revealed 549 differentially expressed genes associated with the presence of CTCcls. Apoptosis was one of the significantly downregulated pathways (normalized enrichment score (NES) = −1.69; FDR < 0.05) in TNBC PDX tumors associated with CTCcl positivity. Two out of four CTCcl+ TNBC PDX primary tumors had high Bcl2 expression by IHC (H-score > 34); whereas, only one of six CTCcl− TNBC PDX primary tumors met this criterion. Evaluation of epithelial-mesenchymal transition (EMT)-specific signature did not show significant differences between CTCcl+ and CTCcl− tumors. However, a gene signature associated with the presence of CTCcls in TNBC PDX models was associated with worse relapse-free survival in the publicly available dataset from 360 patients with basal-like BC. In summary, we identified the multigene signature of primary PDX tumors associated with the presence of CTCcls. Evaluation of additional TNBC PDX models and patients can further illuminate cellular and molecular pathways facilitating CTCcl formation. MDPI 2019-10-24 /pmc/articles/PMC6912280/ /pubmed/31652963 http://dx.doi.org/10.3390/jcm8111772 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Thangavel, Hariprasad
Angelis, Carmine De
Vasaikar, Suhas
Bhat, Raksha
Jolly, Mohit Kumar
Nagi, Chandandeep
Creighton, Chad J.
Chen, Fengju
Dobrolecki, Lacey E.
George, Jason T.
Kumar, Tanya
Abdulkareem, Noor Mazin
Mao, Sufeng
Nardone, Agostina
Rimawi, Mothaffar
Osborne, C. Kent
Lewis, Michael T.
Levine, Herbert
Zhang, Bing
Schiff, Rachel
Giuliano, Mario
Trivedi, Meghana V.
A CTC-Cluster-Specific Signature Derived from OMICS Analysis of Patient-Derived Xenograft Tumors Predicts Outcomes in Basal-Like Breast Cancer
title A CTC-Cluster-Specific Signature Derived from OMICS Analysis of Patient-Derived Xenograft Tumors Predicts Outcomes in Basal-Like Breast Cancer
title_full A CTC-Cluster-Specific Signature Derived from OMICS Analysis of Patient-Derived Xenograft Tumors Predicts Outcomes in Basal-Like Breast Cancer
title_fullStr A CTC-Cluster-Specific Signature Derived from OMICS Analysis of Patient-Derived Xenograft Tumors Predicts Outcomes in Basal-Like Breast Cancer
title_full_unstemmed A CTC-Cluster-Specific Signature Derived from OMICS Analysis of Patient-Derived Xenograft Tumors Predicts Outcomes in Basal-Like Breast Cancer
title_short A CTC-Cluster-Specific Signature Derived from OMICS Analysis of Patient-Derived Xenograft Tumors Predicts Outcomes in Basal-Like Breast Cancer
title_sort ctc-cluster-specific signature derived from omics analysis of patient-derived xenograft tumors predicts outcomes in basal-like breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912280/
https://www.ncbi.nlm.nih.gov/pubmed/31652963
http://dx.doi.org/10.3390/jcm8111772
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