The cardiac lncRNA Chantico directly regulates Cxcl1 chemokine transcription

In local gene regulation, long noncoding RNA (lncRNA) loci can function at three distinct, but non-mutually exclusive levels: the RNA molecule itself, the process of its transcription, and/or the underlying DNA element. Yet for cis-acting lncRNA, these distinctions are particularly challenging with present tools. To address this problem, we developed Omegazymes, catalytic nucleic acid enzymes to specifically target lncRNA for degradation without triggering premature termination of their transcription. We use Omegazymes to selectively target one of a highly refined set of lncRNAs in the mouse cardiomyocytes, demonstrating that the Chantico lncRNA molecule directly potentiates the transcription of Cxcl1, a neighboring chemokine gene. We find that the Chantico locus also acts at the DNA-level, as the binding of an essential cardiac transcription factor to the Chantico promoter is necessary for Cxcl1 transcription in mature cardiomyocytes. This Chantico regulation of Cxcl1 impacts cardiomyocyte signaling to immune cells, potentially regulating tissue-residence and inflammation.

12-chemokine gene expression score in breast cancer patients treated with neoadjuvant chemotherapy.

591 Background: Although advances in immunotherapy for the treatment of breast cancer have been minimal compared with other cancers, studies demonstrating tumor-infiltrating lymphocytes and immunomodulatory gene activation in the tumor microenvironment suggest the importance of antitumor immune responses in clinical outcomes. A 12-chemokine gene score has been shown to predict the presence of ectopic lymph node-like structures (ELN) in the tumor microenvironment and improved survival in melanoma, colon cancer, and breast cancer patients (Prabhakaran, 2017). Here, we evaluated this signature in an independent dataset of breast cancer patients treated with neoadjuvant chemotherapy. Methods: Tumor specimens used in this retrospective analysis (n = 92) were from breast cancer patients enrolled in either MINT (NCT0151487) or NBRST (NCT01479101) neoadjuvant registry trials from 2011 to 2016. Clinical data were captured with informed consent, and 70-gene signature (70-GS), 80-gene signature (80-GS), and full transcriptome data were generated by Agendia, Inc. Gene expression data were quantile normalized using R limma package. Principal component analysis (PCA) was performed on the normalized dataset using R princomp package. Chemokine score (CS) was defined as the first principal component values resulting from PCA. 70-GS/80-GS and clinical data were evaluated in relation to CS. CS were compared using Mann-Whitney test. Results: Of 92 breast tumors available for analysis, 84% were 70-GS High Risk (HR). Tumors were 39% Luminal-type, 24% HER2-type, and 32% Basal-type by 80-GS. HR tumors had higher CS than 70-GS Low Risk (LR) tumors (p < 0.001). 80-GS Basal-type, HER2-type, and Luminal B tumors had higher CS than Luminal A tumors (p < 0.01 for each comparison). High grade and ER-negative tumors seemed to have a high CS, although not significantly. Tumors from patients who achieved a pathological complete response (pCR) following neoadjuvant chemotherapy had higher CS than patients with residual cancer burden (p = 0.048). Conclusions: The current study demonstrated a significantly higher CS in 70-GS HR tumors and those which achieved pCR following neoadjuvant chemotherapy. Although further study is needed to evaluate the association of high CS with tumor-associated ELN, these results support previous work demonstrating that, although high CS is associated with aggressive clinical features, it also predicts superior clinical outcomes. The current study suggests validation of the 12-chemokine gene score in an independent dataset of breast cancer patients.