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J Clin Med. 2019 Oct 24;8(11). pii: E1772. doi: 10.3390/jcm8111772.

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

Thangavel H1, Angelis C2,3, Vasaikar S4, Bhat R5, Jolly MK6,7, Nagi C8, Creighton CJ9, Chen F10, Dobrolecki LE11, George JT12,13, Kumar T14, Abdulkareem NM15,16, Mao S17, Nardone A18,19, Rimawi M20,21,22, Osborne CK23,24,25, Lewis MT26,27,28, Levine H29,30, Zhang B31,32,33, Schiff R34,35,36,37, Giuliano M38,39, Trivedi MV40,41,42,43,44.

Author information

1
Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX 77204, USA. hthangav@central.uh.edu.
2
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA. carmine.deangelis@bcm.edu.
3
Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy. carmine.deangelis@bcm.edu.
4
Department of Translational Molecular Pathology, MD Anderson Cancer Research Center, Houston, TX 77030, USA. svvasaikar@mdanderson.org.
5
Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX 77204, USA. rrbhat2@central.uh.edu.
6
Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India. mkjolly@iisc.ac.in.
7
Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA. mkjolly@iisc.ac.in.
8
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA. chandandeep.nagi@bcm.edu.
9
Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. creighto@bcm.edu.
10
Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. fengjuc@bcm.edu.
11
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA. dobrolec@bcm.edu.
12
Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA. jason.george@rice.edu.
13
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. jason.george@rice.edu.
14
Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX 77204, USA. tkumar5@uh.edu.
15
Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX 77204, USA. nabdulka@central.uh.edu.
16
Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX 77204, USA. nabdulka@central.uh.edu.
17
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA. smao@bcm.edu.
18
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA. nardone@bcm.edu.
19
Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, MA 02215, USA. nardone@bcm.edu.
20
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA. rimawi@bcm.edu.
21
Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. rimawi@bcm.edu.
22
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. rimawi@bcm.edu.
23
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA. kosborne@bcm.edu.
24
Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. kosborne@bcm.edu.
25
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. kosborne@bcm.edu.
26
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA. mtlewis@bcm.edu.
27
Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. mtlewis@bcm.edu.
28
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. mtlewis@bcm.edu.
29
Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA. h.levine@northeastern.edu.
30
Department of Bioengineering, Northeastern University, Boston, MA 02120, USA. h.levine@northeastern.edu.
31
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA. bing.zhang@bcm.edu.
32
Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. bing.zhang@bcm.edu.
33
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. bing.zhang@bcm.edu.
34
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA. rschiff@bcm.edu.
35
Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. rschiff@bcm.edu.
36
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. rschiff@bcm.edu.
37
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. rschiff@bcm.edu.
38
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA. m.giuliano@unina.it.
39
Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy. m.giuliano@unina.it.
40
Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX 77204, USA. mtrivedi@central.uh.edu.
41
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA. mtrivedi@central.uh.edu.
42
Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. mtrivedi@central.uh.edu.
43
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. mtrivedi@central.uh.edu.
44
Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX 77204, USA. mtrivedi@central.uh.edu.

Abstract

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.

KEYWORDS:

B-cell lymphoma 2; CTC clusters; RPPA; apoptosis; circulating tumor cells; patient-derived xenograft; transcriptomics; triple-negative breast cancer

PMID:
31652963
DOI:
10.3390/jcm8111772
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