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

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

doi:10.1016/j.stem.2017.12.009

Cited by 445 publications

(538 citation statements)

References 48 publications

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“…In contrast to the healthy FT epithelium (Kessler et al , ), we find that HGSOC cancer organoids require a low‐Wnt signaling environment but an active BMP signaling axis. Wnt independence was previously observed in other cancers such as pancreas and colon (Fujii et al , ; Seino et al , ) and positively correlates with the clinical progression. However, in contrast to organoids from other cancers, e.g., metastatic pancreatic cancer, which do not require Wnt but do grow in Wnt/RSPO/Noggin medium, exogenous supplementation of Wnt3a actually prevented formation and growth of all HGSOC cancer organoids.…”

Section: Discussionmentioning

confidence: 60%

Stable expansion of high‐grade serous ovarian cancer organoids requires a low‐Wnt environment

et al. 2020

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High‐grade serous ovarian cancer (HGSOC) likely originates from the fallopian tube (FT) epithelium. Here, we established 15 organoid lines from HGSOC primary tumor deposits that closely match the mutational profile and phenotype of the parental tumor. We found that Wnt pathway activation leads to growth arrest of these cancer organoids. Moreover, active BMP signaling is almost always required for the generation of HGSOC organoids, while healthy fallopian tube organoids depend on BMP suppression by Noggin. Fallopian tube organoids modified by stable shRNA knockdown of p53, PTEN, and retinoblastoma protein (RB) also require a low‐Wnt environment for long‐term growth, while fallopian tube organoid medium triggers growth arrest. Thus, early changes in the stem cell niche environment are needed to support outgrowth of these genetically altered cells. Indeed, comparative analysis of gene expression pattern and phenotypes of normal vs. loss‐of‐function organoids confirmed that depletion of tumor suppressors triggers changes in the regulation of stemness and differentiation.

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Section: Discussionmentioning

confidence: 60%

Stable expansion of high‐grade serous ovarian cancer organoids requires a low‐Wnt environment

et al. 2020

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“…Although our data indicate that WNT5A overexpression in tumor cells functions in a cellautonomous manner to activate YAP1 oncoprotein, tumor cells may also activate WNT5A signaling through paracrine mechanisms. Notably, WNT5A has been shown to be highly expressed in PDAC stroma fibroblast (46,47), and our preliminary data suggest that the stromal WNT5A level is significantly correlated with tumor cell YAP1 level in human PDAC (data not shown).…”

Section: Discussionmentioning

confidence: 70%

YAP1 oncogene is a context-specific driver for pancreatic ductal adenocarcinoma

Yao

et al. 2018

Preprint

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Transcriptomic profiling classifies pancreatic ductal adenocarcinoma (PDAC) into several molecular subtypes with distinctive histological and clinical characteristics. However, little is known about the molecular mechanisms that define each subtype and their correlation with clinical outcome. Mutant KRAS is the most prominent driver in PDAC, present in over 90% of tumors, but the dependence of tumors on oncogenic KRAS signaling varies between subtypes. In particular, squamous subtype are relatively independent of oncogenic KRAS signaling and typically display much more aggressive clinical behavior versus progenitor subtype. Here, we identified that YAP1 activation is enriched in the squamous subtype and associated with poor prognosis. Activation of YAP1 in progenitor subtype cancer cells profoundly enhanced malignant phenotypes and transformed progenitor subtype cells into squamous subtype. Conversely, depletion of YAP1 specifically suppressed tumorigenicity of squamous subtype PDAC cells. Mechanistically, we uncovered a significant positive correlation between WNT5A expression and the YAP1 activity in human PDAC, and demonstrated that WNT5A overexpression led to YAP1 activation and recapitulated YAP1-dependent but Kras-independent phenotype of tumor progression and maintenance. Thus, our study identifies YAP1 oncogene as a major driver of squamous subtype PDAC and uncovers the role of WNT5A in driving PDAC malignancy through activation of the YAP pathway.

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“…In principle, pheno-seq can be applied to any 3D-culture system given that the phenotypic identity is maintained upon spheroid isolation. For example, morphologies of organoids derived from patients with pancreatic ductal adenocarcinoma can be linked to the state of malignant transformation and prognosis 46 . We expect that this combination of functional single cell growth assay with combined image and gene expression profiling will be widely applied in cancer biology, ranging from primary to circulating tumor cells (CTCs 47 ).…”

Section: Discussionmentioning

confidence: 99%

pheno-seq – linking morphological features to gene expression in 3D cell culture systems

Tirier

Park

Preußer

et al. 2018

Preprint

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3D-culture systems have advanced cancer modeling by reflecting physiological characteristics of in-vivo tissues, but our understanding of functional intratumor heterogeneity including visual phenotypes and underlying gene expression is still limited. Single-cell RNA-sequencing is the method of choice to dissect transcriptional tumor cell heterogeneity in an unbiased way, but this approach is limited in correlating gene expression with contextual cellular phenotypes.To link morphological features and gene expression in 3D-culture systems, we present 'pheno-seq' for integrated high-throughput imaging and transcriptomic profiling of clonal tumor spheroids. Specifically, we identify characteristic EMT expression signatures that are associated with invasive growth behavior in a 3D breast cancer model. Additionally, pheno-seq determined transcriptional programs containing lineage-specific markers that can be linked to heterogeneous proliferative capacity in a patient-derived 3D model of colorectal cancer. Finally, we provide evidence that pheno-seq identifies morphology-specific genes that are missed by scRNA-seq and inferred single-cell regulatory states without acquiring additional single cell expression profiles. We anticipate that directly linking molecular features with patho-phenotypes of cancer cells will improve the understanding of intratumor heterogeneity and consequently be useful for translational research.3

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

Cited by 445 publications

References 48 publications

Stable expansion of high‐grade serous ovarian cancer organoids requires a low‐Wnt environment

Stable expansion of high‐grade serous ovarian cancer organoids requires a low‐Wnt environment

YAP1 oncogene is a context-specific driver for pancreatic ductal adenocarcinoma

pheno-seq – linking morphological features to gene expression in 3D cell culture systems

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