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

Abstract

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 in silico 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.

SIGNIFICANCE:

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.

• Authors: Samantha Guinn, Benedict Kinny-Köster, Joseph A Tandurella, Jacob T Mitchell, Dimitrios N Sidiropoulos, 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 Wolfgang, Jun Yu, Lei Zheng, David P Ryan, David T Ting, Alec Kimmelman, Anuj Gupta, Ludmila Danilova, Jennifer H Elisseeff, Laura D Wood, Genevieve Stein-O'Brien, Luciane T Kagohara, Elizabeth M Jaffee, Richard A Burkhart, Elana J Fertig, Jacquelyn W Zimmerman
• Journal: Cancer research (Cancer Res) Vol. 84 Issue 9 Pg. 1517-1533 (May 02 2024) ISSN: 1538-7445 [Electronic] United States
• PMID: 38587552 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: ©2024 American Association for Cancer Research.

Chemical References

• Integrin beta1
• Itgb1 protein, human
• Vascular Endothelial Growth Factor A
• VEGFA protein, human
• Neuropilin-1

Topics

• Humans
• Epithelial-Mesenchymal Transition
• Carcinoma, Pancreatic Ductal (pathology, metabolism, genetics)
• Cancer-Associated Fibroblasts (metabolism, pathology)
• Pancreatic Neoplasms (pathology, metabolism, genetics)
• Inflammation (pathology, metabolism)
• Tumor Microenvironment
• Integrin beta1 (metabolism, genetics)
• Coculture Techniques
• Single-Cell Analysis
• Organoids (pathology, metabolism)
• Vascular Endothelial Growth Factor A (metabolism, genetics)
• Neuropilin-1 (metabolism, genetics)
• Gene Expression Regulation, Neoplastic
• Cell Line, Tumor
• Cell Communication