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

Herbert Levine¹  JasonT. George¹  MohitKumar Jolly²  Fengju Chen³  ChadJ. Creighton³  Hariprasad Thangavel⁴  MeghanaV. Trivedi⁴  Raksha Bhat⁴  NoorMazin Abdulkareem⁴  Tanya Kumar⁴  Suhas Vasaikar⁵  CarmineDe Angelis⁶  Chandandeep Nagi⁶  MichaelT. Lewis⁶  Sufeng Mao⁶  Bing Zhang⁶  Rachel Schiff⁶  LaceyE. Dobrolecki⁶  C.Kent Osborne⁶  Mothaffar Rimawi⁶  Agostina Nardone⁶  Mario Giuliano⁶ 

[1] Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA;Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India;Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA;Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX 77204, USA;Department of Translational Molecular Pathology, MD Anderson Cancer Research Center, Houston, TX 77030, USA;Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA;

关键词: circulating tumor cells;    ctc clusters;    triple-negative breast cancer;    patient-derived xenograft;    rppa;    transcriptomics;    b-cell lymphoma 2;    apoptosis;   

DOI  :  10.3390/jcm8111772

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown