Abstract 2783: OMICS analysis of breast cancer PDX tumors to determine CTC-cluster-specific signature in predicting breast cancer metastasis
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AbstractCirculating tumor cell clusters (CTCcl) have been shown to have a significantly higher metastatic potential compared to single CTCs and to predict long-term outcomes in breast cancer patients. A characterization of primary tumors that give rise to CTCcl hold significant promises for better diagnosis and may uncover targets for prevention and treatment of metastatic breast cancer. In our study, we utilized the available transcriptomic and proteomic data (RNA-Seq and RPPA) of 10 triple-negative breast cancer patient-derived xenograft (TNBC-PDX) transplantable models. The sample set consisted of 6 CTCcl-negative (-) and 4 CTCcl-positive (+) models. Genome-wide transcriptomic analysis revealed 549 differentially expressed genes in CTCcl+ TNBC-PDX models vs. CTCcl- models (316 up-regulated and 233 down-regulated, p>0.05). Gene set enrichment analysis (GSEA) terms significantly enriched (FDR>0.05) in CTCcl+ TNBC-PDXs included Cytoplasmic Ribosomal Proteins (NES=2.53), Angiogenesis (NES=1.95), Type II Interferon signaling (NES=-2.52), Antigen processing and presentation (NES=-2.38), TNF signaling pathway (NES=-2.04), Jak-STAT signaling pathway (NES=-1.91), and apoptosis (NES=-1.69). The proteomic analysis revealed elevated levels of Bcl2 expression in PDX tumors associated with CTCcl positivity, which substantiated the inhibited apoptosis pathway as seen in GSEA analysis. The increase in Bcl2 was also validated independently by IHC staining in primary PDX tumors that were CTCcl+. The distribution of EMT score based on the inferential EMT metric using canonical epithelial and mesenchymal markers was not significantly different between CTCcl+ and CTCcl- TNBC-PDX tumors suggesting no differential regulation of EMT in tumors that give rise to clusters versus only single cells. In summary, our results suggest that primary tumors with active anti-apoptotic and/or survival pathways may promote CTC clusters formation and increase the risk of distant metastasis.Citation Format: Hariprasad Thangavel, Carmine De Angelis, Suhas Vasaikar, Raksha Bhat, Mohit Kumar Jolly, Lacey Elizabeth Dobrolecki, Jason T. George, Mario Giuliano, Michael Lewis, Herbert Levine, Bing Zhang, Rachel Schiff, Meghana V. Trivedi. OMICS analysis of breast cancer PDX tumors to determine CTC-cluster-specific signature in predicting breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2783.
