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Cell Stem Cell. 2018 Mar 1;22(3):454-467.e6. doi: 10.1016/j.stem.2017.12.009. Epub 2018 Jan 11.

Human Pancreatic Tumor Organoids Reveal Loss of Stem Cell Niche Factor Dependence during Disease Progression.

Author information

1
Department of Gastroenterology, Keio University School of Medicine, Tokyo 160-8582, Japan.
2
Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Suita 565-0871, Japan.
3
Department of Gastroenterology, Tokyo Medical University, Tokyo 160-0023, Japan.
4
Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.
5
Department of Gastroenterology, Keio University School of Medicine, Tokyo 160-8582, Japan. Electronic address: t.sato@keio.jp.

Abstract

Despite recent efforts to dissect the inter-tumor heterogeneity of pancreatic ductal adenocarcinoma (PDAC) by determining prognosis-predictive gene expression signatures for specific subtypes, their functional differences remain elusive. Here, we established a pancreatic tumor organoid library encompassing 39 patient-derived PDACs and identified 3 functional subtypes based on their stem cell niche factor dependencies on Wnt and R-spondin. A Wnt-non-producing subtype required Wnt from cancer-associated fibroblasts, whereas a Wnt-producing subtype autonomously secreted Wnt ligands and an R-spondin-independent subtype grew in the absence of Wnt and R-spondin. Transcriptome analysis of PDAC organoids revealed gene-expression signatures that associated Wnt niche subtypes with GATA6-dependent gene expression subtypes, which were functionally supported by genetic perturbation of GATA6. Furthermore, CRISPR-Cas9-based genome editing of PDAC driver genes (KRAS, CDKN2A, SMAD4, and TP53) demonstrated non-genetic acquisition of Wnt niche independence during pancreas tumorigenesis. Collectively, our results reveal functional heterogeneity of Wnt niche independency in PDAC that is non-genetically formed through tumor progression.

KEYWORDS:

CRISPR-Cas9; GATA6; Wnt; organoids; pancreatic cancer; stem cell niche

PMID:
29337182
DOI:
10.1016/j.stem.2017.12.009
[Indexed for MEDLINE]
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