Data from Transfer Learning Reveals Cancer-Associated Fibroblasts Are Associated with Epithelial–Mesenchymal Transition and Inflammation in Cancer Cells in Pancreatic Ductal Adenocarcinoma

• DOI: 10.1158/0008-5472.c.7213937
• Publication Date: 2024-05-02T07:49:04Z
• Authors: Samantha Guinn; Benedict Kinny-Kö...; Joseph A. Tandurella; Jacob T. Mitchell; Dimitrios N. Sidi...; Melanie Loth; Melissa R. Lyman; Alexandra B. Pucsek; Daniel J. Zabransky; Jae W. Lee; Emma Kartalia; Mili Ramani; Toni T. Seppälä; Christopher Cherry; Reecha Suri; Haley Zlomke; Jignasha Patel; Jin He; Christopher L. Wo...; Jun Yu; Lei Zheng; David P. Ryan; David T. Ting; Alec Kimmelman; Anuj Gupta; Ludmila Danilova; Jennifer H. Eliss...; Laura D. Wood; Genevieve Stein-O...; Luciane T. Kagohara; Elizabeth M. Jaffee; Richard A. Burkhart; Elana J. Fertig; Jacquelyn W. Zimm...

<div>Abstract<p>Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by an immunosuppressive tumor microenvironment enriched with cancer-associated fibroblasts (CAF). This study used a convergence approach to identify tumor cell and CAF interactions through the integration of single-cell data from human tumors with human organoid coculture experiments. Analysis of a comprehensive atlas of PDAC single-cell RNA sequencing data indicated that CAF density is associated with increased inflammation and epithelial–mesenchymal transition (EMT) in epithelial cells. Transfer learning using transcriptional data from patient-derived organoid and CAF cocultures provided <i>in silico</i> validation of CAF induction of inflammatory and EMT epithelial cell states. Further experimental validation in cocultures demonstrated integrin beta 1 (ITGB1) and vascular endothelial factor A (VEGFA) interactions with neuropilin-1 mediating CAF-epithelial cell cross-talk. Together, this study introduces transfer learning from human single-cell data to organoid coculture analyses for experimental validation of discoveries of cell–cell cross-talk and identifies fibroblast-mediated regulation of EMT and inflammation.</p>Significance:<p>Adaptation of transfer learning to relate human single-cell RNA sequencing data to organoid-CAF cocultures facilitates discovery of human pancreatic cancer intercellular interactions and uncovers cross-talk between CAFs and tumor cells through VEGFA and ITGB1.</p></div>