Abstract 4033: Suppressive role of normal epithelium in pre-malignant to malignant progression of Barrett's esophagus

Abstract

Abstract Cell-cell communication plays a central role in cellular function under normal and diseased conditions. In cancer, intercellular interactions are highly complex and remain poorly understood, particularly with respect to the early events leading to the transformation from benign to malignant phenotypes. In early stages of carcinogenesis, normal and transformed cells often coexist in close proximity, suggesting that interactions between them influence progression. Comprehensive understanding of these events is critical in identifying new therapeutic targets and devising novel treatment strategies. We studied the functional relevance of intercellular interactions between normal and pre-malignant epithelial cells using an in vitro model of Barrett's esophagus (BE) progression from pre-malignant epithelium to esophageal adenocarcinoma. BE provides an ideal disease model to explore the interaction between cells at different stages of neoplastic transformation because it can be prospectively followed. Thus, studies performed in in vitro and animal models can be readily extended to the clinic. We investigated the effects of heterotypic interactions between normal and dysplastic (pre-malignant) esophageal epithelial cells at the single-cell and bulk-cell level. We found that the dysplastic cells were affected to a larger extent than normal cells in terms of gene expression levels and cellular function. Analysis of the RNA-seq data revealed a total of 809 genes differentially expressed in dysplastic cells as compared with 234 genes differentially expressed in normal cells. Functional enrichment analysis identified the following 5 top functional categories in dysplastic cells affected (downregulated) by interactions with normal epithelial cells: cellular movement, tissue morphology, cancer, lipid metabolism and molecular transport. Functional assays revealed a significant repression of the proliferation rates (up to 6-fold) of both cell types, but only dysplastic cells showed significant motility changes (speed, displacement and directionality) as a result of interactions between the two cell types. The decrease in the proliferation rate of dysplastic cells indicates a strong suppressor role of normal epithelial cells mediated by repression of TGFβ and EGF signaling in pre-malignant progression in BE. At the single-cell level, we present both metabolic and expression-level profiles of a panel of selected genes in individual normal and dysplastic cells, and compare them with bulk-cell measurements. These findings indicate that attenuation of the TGFβ and EGF signaling pathways in the presence of normal epithelial cells may play an important role in suppressing the growth of pre-malignant epithelial cells. Hence, both TGFβ and EGF may serve as biomarkers for progression from pre-malignant to malignant phenotype in epithelial cells. Citation Format: Laimonas Kelbauskas, Jia Zeng, Aida Rezaie, Kristen Lee, Benjamin Ueberroth, Weimin Gao, Dmitry Derkach, Colleen Ziegler, Thai Tran, Kimberly J. Bussey, Dean Smith, Roger H. Johnson, Deirdre R. Meldrum. Suppressive role of normal epithelium in pre-malignant to malignant progression of Barrett's esophagus. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4033. doi:10.1158/1538-7445.AM2015-4033