Unsupervised class discovery in pancreatic ductal adenocarcinoma reveals cell-intrinsic mesenchymal features and high concordance between existing classification systems.
Adult
Aged
Aged, 80 and over
Animals
Carcinoma, Pancreatic Ductal
/ classification
Female
Humans
Kaplan-Meier Estimate
Male
Mice
Middle Aged
Pancreatic Neoplasms
/ classification
Prognosis
Proportional Hazards Models
Sequence Analysis, RNA
Tandem Repeat Sequences
Transplantation, Heterologous
Pancreatic Neoplasms
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
15 01 2020
15 01 2020
Historique:
received:
17
07
2019
accepted:
17
12
2019
entrez:
17
1
2020
pubmed:
17
1
2020
medline:
11
11
2020
Statut:
epublish
Résumé
Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all common cancers. However, divergent outcomes exist between patients, suggesting distinct underlying tumor biology. Here, we delineated this heterogeneity, compared interconnectivity between classification systems, and experimentally addressed the tumor biology that drives poor outcome. RNA-sequencing of 90 resected specimens and unsupervised classification revealed four subgroups associated with distinct outcomes. The worst-prognosis subtype was characterized by mesenchymal gene signatures. Comparative (network) analysis showed high interconnectivity with previously identified classification schemes and high robustness of the mesenchymal subtype. From species-specific transcript analysis of matching patient-derived xenografts we constructed dedicated classifiers for experimental models. Detailed assessments of tumor growth in subtyped experimental models revealed that a highly invasive growth pattern of mesenchymal subtype tumor cells is responsible for its poor outcome. Concluding, by developing a classification system tailored to experimental models, we have uncovered subtype-specific biology that should be further explored to improve treatment of a group of PDAC patients that currently has little therapeutic benefit from surgical treatment.
Identifiants
pubmed: 31941932
doi: 10.1038/s41598-019-56826-9
pii: 10.1038/s41598-019-56826-9
pmc: PMC6962149
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
337Références
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