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Article

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

1
Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX 77204, USA
2
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
3
Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy
4
Department of Translational Molecular Pathology, MD Anderson Cancer Research Center, Houston, TX 77030, USA
5
Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India
6
Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA
7
Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
8
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
9
Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX 77204, USA
10
Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, MA 02215, USA
11
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
12
Department of Bioengineering, Northeastern University, Boston, MA 02120, USA
*
Author to whom correspondence should be addressed.
Co-first authors, these authors contributed equally to this work.
J. Clin. Med. 2019, 8(11), 1772; https://doi.org/10.3390/jcm8111772
Received: 18 September 2019 / Revised: 12 October 2019 / Accepted: 21 October 2019 / Published: 24 October 2019
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. View Full-Text
Keywords: circulating tumor cells; CTC clusters; triple-negative breast cancer; patient-derived xenograft; RPPA; transcriptomics; B-cell lymphoma 2; apoptosis circulating tumor cells; CTC clusters; triple-negative breast cancer; patient-derived xenograft; RPPA; transcriptomics; B-cell lymphoma 2; apoptosis
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MDPI and ACS Style

Thangavel, H.; Angelis, C.D.; Vasaikar, S.; Bhat, R.; Jolly, M.K.; Nagi, C.; Creighton, C.J.; Chen, F.; Dobrolecki, L.E.; George, J.T.; Kumar, T.; Abdulkareem, N.M.; Mao, S.; Nardone, A.; Rimawi, M.; Osborne, C.K.; Lewis, M.T.; Levine, H.; Zhang, B.; Schiff, R.; Giuliano, M.; Trivedi, M.V. A CTC-Cluster-Specific Signature Derived from OMICS Analysis of Patient-Derived Xenograft Tumors Predicts Outcomes in Basal-Like Breast Cancer. J. Clin. Med. 2019, 8, 1772. https://doi.org/10.3390/jcm8111772

AMA Style

Thangavel H, Angelis CD, Vasaikar S, Bhat R, Jolly MK, Nagi C, Creighton CJ, Chen F, Dobrolecki LE, George JT, Kumar T, Abdulkareem NM, Mao S, Nardone A, Rimawi M, Osborne CK, Lewis MT, Levine H, Zhang B, Schiff R, Giuliano M, Trivedi MV. A CTC-Cluster-Specific Signature Derived from OMICS Analysis of Patient-Derived Xenograft Tumors Predicts Outcomes in Basal-Like Breast Cancer. Journal of Clinical Medicine. 2019; 8(11):1772. https://doi.org/10.3390/jcm8111772

Chicago/Turabian Style

Thangavel, Hariprasad, Carmine D. Angelis, Suhas Vasaikar, Raksha Bhat, Mohit K. Jolly, Chandandeep Nagi, Chad J. Creighton, Fengju Chen, Lacey E. Dobrolecki, Jason T. George, Tanya Kumar, Noor M. Abdulkareem, Sufeng Mao, Agostina Nardone, Mothaffar Rimawi, C. K. Osborne, Michael T. Lewis, Herbert Levine, Bing Zhang, Rachel Schiff, Mario Giuliano, and Meghana V. Trivedi 2019. "A CTC-Cluster-Specific Signature Derived from OMICS Analysis of Patient-Derived Xenograft Tumors Predicts Outcomes in Basal-Like Breast Cancer" Journal of Clinical Medicine 8, no. 11: 1772. https://doi.org/10.3390/jcm8111772

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