TY - JOUR
T1 - Transfer Learning Reveals Cancer-Associated Fibroblasts Are Associated with Epithelial–Mesenchymal Transition and Inflammation in Cancer Cells in Pancreatic Ductal Adenocarcinoma
AU - Guinn, Samantha
AU - Kinny-Köster, Benedict
AU - Tandurella, Joseph A.
AU - Mitchell, Jacob T.
AU - Sidiropoulos, Dimitrios N.
AU - Loth, Melanie
AU - Lyman, Melissa R.
AU - Pucsek, Alexandra B.
AU - Zabransky, Daniel J.
AU - Lee, Jae W.
AU - Kartalia, Emma
AU - Ramani, Mili
AU - Seppälä, Toni T.
AU - Cherry, Christopher
AU - Suri, Reecha
AU - Zlomke, Haley
AU - Patel, Jignasha
AU - He, Jin
AU - Wolfgang, Christopher L.
AU - Yu, Jun
AU - Zheng, Lei
AU - Ryan, David P.
AU - Ting, David T.
AU - Kimmelman, Alec
AU - Gupta, Anuj
AU - Danilova, Ludmila
AU - Elisseeff, Jennifer H.
AU - Wood, Laura D.
AU - Stein-O’Brien, Genevieve
AU - Kagohara, Luciane T.
AU - Jaffee, Elizabeth M.
AU - Burkhart, Richard A.
AU - Fertig, Elana J.
AU - Zimmerman, Jacquelyn W.
N1 - Publisher Copyright:
©2024 American Association for Cancer Research.
PY - 2024/5/1
Y1 - 2024/5/1
N2 - 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 crosstalk. 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.
AB - 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 crosstalk. 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.
UR - https://www.scopus.com/pages/publications/85192114247
UR - https://www.scopus.com/pages/publications/85192114247#tab=citedBy
U2 - 10.1158/0008-5472.CAN-23-1660
DO - 10.1158/0008-5472.CAN-23-1660
M3 - Article
C2 - 38587552
AN - SCOPUS:85192114247
SN - 0008-5472
VL - 84
SP - 1517
EP - 1533
JO - Cancer Research
JF - Cancer Research
IS - 9
ER -