Abstract A54: A cellular and molecular atlas of the human breast for dissecting mechanisms of cell and tissue function

Abstract

Abstract A fundamental question in biology, central to our understanding of cancer, is determining how cells coordinate and cooperate to form and maintain tissues. Developing systems-wide knowledge of the numerous cell interactions within a tissue requires robust identification of the cell types it comprises. It demands comprehensive information about each of these cell types, including the genes they express and proteins they make. Unfortunately, the cellular composition and arrangement of cells in many complex tissue systems has yet to be fully resolved, and this includes the breast. This has resulted in a crucial knowledge gap where we know very little about the elaborate biology of how different normal cell types interact, and the consequences these interactions have on each other and the tissue as a whole. Using immunofluorescence and advanced flow cytometry, we have recently developed methods to resolve and isolate every known cell type in the normal human breast. This includes several different luminal and epithelial fractions, myoepithelial cells, adipocytes, leukocytes, pericytes, erythrocytes, adipose-derived mesenchymal stem cells, vascular smooth muscle cells, and both lymphatic and vascular endothelial cells—12 different types in all. Successful modification of this multiparameter FACS procedure allowed purification of enough cells and RNA to perform next-generation sequencing (NGS) from even the rarest of populations at high depth. Here, we present global transcriptome analysis of these different cell types. These data have clarified cell-type differences and revealed new insights, including the identification of genes and gene families contributing to the unique phenotype of each cell type and the delineation of lineage-specific marker expression. Our analysis has also exposed how the cell types each contribute to their individual microenvironments through production of extracellular matrix proteins and other secreted factors. Moreover, identification of cognate ligand and receptor pairs expressed by these cells has unveiled an elaborate paracrine and autocrine signaling network that has implications towards interpreting the biologic interactome underlying tissue homeostasis. Future studies are aimed at establishing coculture models and determining the biochemical processes essential for cell-coordination and tissue maintenance, and developing knowledge of how these processes go awry in breast cancer. Citation Format: Rosalyn W. Sayaman, Ambrose Carr, Kate Thi, Zhenmao Wan, Dana Pe’er, Mina J. Bissell, Curt Hines. A cellular and molecular atlas of the human breast for dissecting mechanisms of cell and tissue function [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A54.