Abstract
Abstract Cellular heterogeneity poses a significant challenge to understanding tissue level phenotypes, and confounds conventional bulk analyses. To facilitate the analysis of signaling at the single-cell level in human tissues, we, for the first time, applied mass cytometry using CyTOF (Cytometry Time-of-Flight) to formalin-fixed paraffin-embedded (FFPE) normal and diseased intestinal specimens. We developed and validated FFPE-DISSECT (Disaggregation for Intracellular Signaling in Single Epithelial Cells from Tissue), a single-cell approach for preserving and characterizing native signaling states from embedded solid tissue samples. We applied FFPE-DISSECT coupled to mass cytometry to demonstrate differential TNF-α signaling in intestinal enterocytes, goblet cells and enteroendocrine cells, implicating the role of the RAS-RAF-MEK-ERK signaling pathway in goblet cell identity. In addition, application of FFPE-DISSECT, mass cytometry, and data-driven computational analyses of human colorectal cancer specimens confirmed reduction of differentiation and revealed quantitative changes in inter- and intra-tumoral heterogeneity with regards to the modular regulation of signaling pathways. Our single-cell approach, applied in conjunction with genomic annotation such as microsatellite and K-Ras and B-RAF status, allows rapid and detailed characterization of cellular heterogeneity from clinical repositories of embedded human tissues. Citation Format: Alan J. Simmons, Cherie R. Scurrah, Eliot T. McKinley, Charles A. Herring, Jonathan M. Irish, Mary K. Washington, Robert J. Coffey, Ken S. Lau. Reorganization of signaling modules revealed in human colorectal cancer using single-cell mass cytometry. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr B29.
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