Transfer learning reveals cancer-associated fibroblasts are associated with epithelial-mesenchymal transition and inflammation in cancer cells in pancreatic ductal adenocarcinoma.
Samantha GuinnBenedict Kinny-KösterJoseph A TandurellaJacob T MitchellDimitrios N SidiropoulosMelanie LothMelissa R LymanAlexandra B PucsekDaniel J ZabranskyJae W LeeEmma KartaliaMili RamaniToni T SeppäläChristopher M CherryReecha SuriHaley ZlomkeJignasha PatelJin HeChristopher L WolfgangXin YuLei ZhengDavid P RyanDavid Tsai TingAlec C KimmelmanAnuj GuptaLudmila V DanilovaJennifer H ElisseeffLaura D WoodGenevieve L Stein-O'BrienLuciane Tsukamoto KagoharaElizabeth D ThompsonRichard Andrew BurkhartElana J FertigJacquelyn W ZimmermanPublished in: Cancer research (2024)
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by an immunosuppressive tumor microenvironment enriched with cancer associated fibroblasts (CAFs). This study utilized a convergence approach to identify tumor cell and CAF interactions through the integration of single-cell data from human tumors with human organoid co-culture experiments. Analysis of a comprehensive atlas of PDAC single-cell RNA sequencing (scRNA-seq) 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 co-cultures provided in silico validation of CAF induction of inflammatory and EMT epithelial cell states. Further experimental validation in co-cultures demonstrated integrin beta 1 (ITGB1) and vascular endothelial factor A (VEGF-A) interactions with neuropilin-1 (NRP1) mediating CAF-epithelial cell crosstalk. Together, this study introduces transfer learning from human single-cell data to organoid co-culture analyses for experimental validation of discoveries of cell-cell crosstalk and identifies fibroblast-mediated regulation of EMT and inflammation.
Keyphrases
- single cell
- epithelial mesenchymal transition
- rna seq
- endothelial cells
- high throughput
- oxidative stress
- electronic health record
- transforming growth factor
- big data
- induced pluripotent stem cells
- signaling pathway
- pluripotent stem cells
- gene expression
- stem cells
- vascular endothelial growth factor
- data analysis
- transcription factor
- extracellular matrix
- artificial intelligence
- molecular docking
- cell therapy
- heat stress
- deep learning
- bone marrow
- heat shock
- molecular dynamics simulations