Stable expansion of high-grade serous ovarian cancer organoids requires a low-Wnt environment.
Carcinogenesis
/ genetics
Cell Differentiation
Disease Progression
Epithelium
/ pathology
Fallopian Tubes
/ pathology
Female
Gene Knockdown Techniques
Humans
Organoids
/ pathology
Ovarian Neoplasms
/ genetics
Phenotype
Stem Cell Niche
Tumor Suppressor Proteins
/ genetics
Wnt Signaling Pathway
/ genetics
BMP signaling
Wnt signaling
patient-derived HGSOC organoids
stemness
tumor suppressor knockdown
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
16 03 2020
16 03 2020
Historique:
received:
14
11
2019
revised:
17
12
2019
accepted:
21
12
2019
pubmed:
6
2
2020
medline:
11
11
2020
entrez:
4
2
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32009247
doi: 10.15252/embj.2019104013
pmc: PMC7073464
doi:
Substances chimiques
Tumor Suppressor Proteins
0
Banques de données
GEO
['GSE125883', 'GSE124766']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e104013Informations de copyright
© 2020 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
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