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

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 2024;84(9):1517-1533

PMID: 38587552

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Abstract

UNLABELLED

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.

Address: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Surgery, New York University Grossman School of Medicine, New York, New York.; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland.; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland.; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere University Hospital, Tampere, Finland.; Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, Maryland.; Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, Maryland.; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Surgery, New York University Grossman School of Medicine, New York, New York.; The Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.; Department of Radiation Oncology at New York University Grossman School of Medicine, NYU Langone Health, New York, New York.; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland.; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland.; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, Maryland.; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, Maryland.; Department of Applied Mathematics and Statistics, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland.

DOI: 10.1158/0008-5472.CAN-23-1660