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

Takashi Seino, Shintaro Kawasaki, Mariko Shimokawa, Hiroki Tamagawa, Kohta Toshimitsu, Masayuki Fujii, Yuki Ohta, Mami Matano, Kosaku Nanki, Kenta Kawasaki, Sirirat Takahashi, Shinya Sugimoto, Eisuke Iwasaki, Junichi Takagi, Takao Itoi, Minoru Kitago, Yuukou Kitagawa, Takanori Kanai, Toshiro Sato

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77 Citations (Scopus)

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. Sato and colleagues established a library of patient-derived pancreas cancer organoids and identified heterogeneous patterns of dependency on Wnt ligands among pancreas cancers. Biological and genetic analyses highlighted GATA6 as a mediator of the Wnt niche requirement, which links pancreatic tumor progression to independence from the stem cell niche.

Original languageEnglish
JournalCell Stem Cell
DOIs
Publication statusAccepted/In press - 2018 Jan 1

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Keywords

  • CRISPR-Cas9
  • GATA6
  • Organoids
  • Pancreatic cancer
  • Stem cell niche
  • Wnt

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

Cite this

Seino, T., Kawasaki, S., Shimokawa, M., Tamagawa, H., Toshimitsu, K., Fujii, M., Ohta, Y., Matano, M., Nanki, K., Kawasaki, K., Takahashi, S., Sugimoto, S., Iwasaki, E., Takagi, J., Itoi, T., Kitago, M., Kitagawa, Y., Kanai, T., & Sato, T. (Accepted/In press). Human Pancreatic Tumor Organoids Reveal Loss of Stem Cell Niche Factor Dependence during Disease Progression. Cell Stem Cell. https://doi.org/10.1016/j.stem.2017.12.009