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Samenvatting
Background & Aims Epithelial tumors generally resemble the cellular architecture of their tissue of origin. However, this link remains largely unexplored in the pancreas.
Methods Using Nanostring GeoMx DSP®, Resolve Molecular Cartography® and Nanostring CosMx®, and integration with single cell RNAseq datasets, we mapped the human pancreatic ductal epithelium in non-neoplastic pancreas, and compared it to pancreatic cancer subtypes.
Results Groups of Keratin-5+ cells among the Pan-Cytokeratin+ cells in the duct have a gene signature reminiscent of stem cells and (supra)basal cells from other tissues. In spatial analysis at single cell resolution, the pancreatic duct manifests as a stratified epithelium comprising a basal and four luminal populations; In large ducts, KRT5+ basal (BAS) cells express ΔNp63 while KRT5+ luminal (LUM)-B cells reside supra-basally and are distinct from the common KRT5- LUM-A cells. LUM-C and LUM-D cells pertain to intercalated ducts and ductal glands, respectively. LUM-A and -C cells express gel-forming mucins while LUM-B cells have membrane-bound MUC4 and MUC16. In cancer, BAS and LUM-B signatures associate with the basal-like pancreatic ductal adenocarcinoma (PDAC) and correlate with lower survival but exhibit a mixed spatial pattern with a diffracted gene signature. In contrast, adenosquamous cancers of the pancreas (ASCP) preserve the normal spatially unmixed identity of LUM-B cells and BAS cells that is regulated by ΔNp63. Next to ΔNp63, conserved drug targets were identified for both populations.
Conclusion This study offers a refined pancreatic tumor classification based on the native ductal architecture, with better preservation of the LUM-B and BAS cell population identity in ASCP than in PDAC, including the conserved drug targets.
Methods Using Nanostring GeoMx DSP®, Resolve Molecular Cartography® and Nanostring CosMx®, and integration with single cell RNAseq datasets, we mapped the human pancreatic ductal epithelium in non-neoplastic pancreas, and compared it to pancreatic cancer subtypes.
Results Groups of Keratin-5+ cells among the Pan-Cytokeratin+ cells in the duct have a gene signature reminiscent of stem cells and (supra)basal cells from other tissues. In spatial analysis at single cell resolution, the pancreatic duct manifests as a stratified epithelium comprising a basal and four luminal populations; In large ducts, KRT5+ basal (BAS) cells express ΔNp63 while KRT5+ luminal (LUM)-B cells reside supra-basally and are distinct from the common KRT5- LUM-A cells. LUM-C and LUM-D cells pertain to intercalated ducts and ductal glands, respectively. LUM-A and -C cells express gel-forming mucins while LUM-B cells have membrane-bound MUC4 and MUC16. In cancer, BAS and LUM-B signatures associate with the basal-like pancreatic ductal adenocarcinoma (PDAC) and correlate with lower survival but exhibit a mixed spatial pattern with a diffracted gene signature. In contrast, adenosquamous cancers of the pancreas (ASCP) preserve the normal spatially unmixed identity of LUM-B cells and BAS cells that is regulated by ΔNp63. Next to ΔNp63, conserved drug targets were identified for both populations.
Conclusion This study offers a refined pancreatic tumor classification based on the native ductal architecture, with better preservation of the LUM-B and BAS cell population identity in ASCP than in PDAC, including the conserved drug targets.
| Originele taal-2 | English |
|---|---|
| Uitgever | Biorxiv |
| Aantal pagina's | 31 |
| DOI's | |
| Status | Published - 19 jan. 2025 |
Projecten
- 1 Actief
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FWOAL1044: Studie van de plasticiteit van exocriene cellen in de pancreas en voetafdrukken daarvan in moleculaire subtypes van pancreaskanker
1/01/22 → 31/12/25
Project: Fundamenteel