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

Posted on 2024-05-02 - 07:45
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.

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FUNDING

Hopper-Belmont Foundation (HBF)

Lustgarten Foundation (The Lustgarten Foundation)

NIH/NCI

Sigrid Juséliuksen Säätiö (Sigrid Jusélius Stiftelse)

Instrumentariumin Tiedesäätiö (Instrumentarium Science Foundation)

Emil Aaltosen Säätiö (Emil Aaltonen Foundation)

Jane and Aatos Erkko Foundation

Relander Foundation (The Relander Foundation)

iCAN precision medicine of the Finnish academy

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AUTHORS (34)

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
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