3D tissue model to patient atlas: dynamic network topology reveals PDAC chemoresistance bottlenecks.
4 affiliations
- 1Department of Bioinformatics, Biocenter, University of Würzburg, Am Hubland, Würzburg, Germany.
- 2Department for Functional Materials in Medicine and Dentistry, University Hospital Würzburg, Würzburg, Germany.
- 3Section for Molecular Medicine of Signal Transduction, Institute of Molecular Medicine, Faculty of Medicine, Martin Luther University Halle-Wittenberg, 06120, Halle (Saale), Germany.
- 4Department of Bioinformatics, Biocenter, University of Würzburg, Am Hubland, Würzburg, Germany. [email protected].
Abstract
Pancreatic ductal adenocarcinoma (PDAC) develops chemoresistance through dynamic cell-state transitions, yet the regulatory network architecture governing drug-tolerant states remains poorly characterised, because static expression snapshots cannot capture how interaction topology evolves along treatment-induced trajectories. We established a 3D PANC-1 tissue model on decellularised porcine intestinal matrix, which reaches patient-like proliferation indices and tissue-niche-specific drug responses, and performed single-cell RNA sequencing across four conditions: control, gemcitabine (GEM), TGF-β1, and their combination. Coupling pseudotime trajectory inference to dynamic protein-protein interaction network analysis, we tracked betweenness centrality continuously across cell-state transitions rather than comparing discrete states. GEM survivors engaged a proliferative programme (E2F1, CDK1, AURKA, TPX2, TOP2A, BIRC5), whereas TGF-β1 induced an independent EMT attractor (SPOCK1, MBOAT2, COL5A1, THBS1, FN1). Where the two converged, an emergent bottleneck appeared: CDK1 betweenness centrality spiked selectively, restrained by CDKN1A (p21) and WEE1, defining an S-phase-persistence state enriched for GEM survivors. Cross-examination in a PDAC atlas of 726,107 cells from 231 patients showed 8.7-fold metastatic enrichment of triple-positive cells. This framework, linking controlled 3D tissue experimentation, single-cell systems analysis and clinical-scale patient data, is applicable to drug resistance across cancer types.
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BibTeX
@article{almasi2026tissue,
title = {{3D tissue model to patient atlas: dynamic network topology reveals PDAC chemoresistance bottlenecks.}},
author = {Maryam Almasi and Jesús Guillermo Nieves Pereira and Thomas Dandekar and Gudrun Dandekar and Johannes Balkenhol},
journal = {NPJ systems biology and applications},
year = {2026},
month = oct,
doi = {10.1038/s41540-026-00830-z},
url = {https://europepmc.org/article/MED/42919864},
note = {CC BY},
}
RIS
TY - JOUR
TI - 3D tissue model to patient atlas: dynamic network topology reveals PDAC chemoresistance bottlenecks.
AU - Maryam Almasi
AU - Jesús Guillermo Nieves Pereira
AU - Thomas Dandekar
AU - Gudrun Dandekar
AU - Johannes Balkenhol
PY - 2026
DA - 2026/10/23
JO - NPJ systems biology and applications
DO - 10.1038/s41540-026-00830-z
UR - https://europepmc.org/article/MED/42919864
AB - Pancreatic ductal adenocarcinoma (PDAC) develops chemoresistance through dynamic cell-state transitions, yet the regulatory network architecture governing drug-tolerant states remains poorly characterised, because static expression snapshots cannot capture how interaction topology evolves along treatment-induced trajectories. We established a 3D PANC-1 tissue model on decellularised porcine intestinal matrix, which reaches patient-like proliferation indices and tissue-niche-specific drug responses, and performed single-cell RNA sequencing across four conditions: control, gemcitabine (GEM), TGF-β1, and their combination. Coupling pseudotime trajectory inference to dynamic protein-protein interaction network analysis, we tracked betweenness centrality continuously across cell-state transitions rather than comparing discrete states. GEM survivors engaged a proliferative programme (E2F1, CDK1, AURKA, TPX2, TOP2A, BIRC5), whereas TGF-β1 induced an independent EMT attractor (SPOCK1, MBOAT2, COL5A1, THBS1, FN1). Where the two converged, an emergent bottleneck appeared: CDK1 betweenness centrality spiked selectively, restrained by CDKN1A (p21) and WEE1, defining an S-phase-persistence state enriched for GEM survivors. Cross-examination in a PDAC atlas of 726,107 cells from 231 patients showed 8.7-fold metastatic enrichment of triple-positive cells. This framework, linking controlled 3D tissue experimentation, single-cell systems analysis and clinical-scale patient data, is applicable to drug resistance across cancer types.
SN - 2056-7189
ER -