Stromal androgen signaling acts as tumor niches to drive prostatic basal epithelial progenitor-initiated oncogenesis.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
02 11 2022
02 11 2022
Historique:
received:
27
05
2022
accepted:
19
10
2022
entrez:
3
11
2022
pubmed:
4
11
2022
medline:
5
11
2022
Statut:
epublish
Résumé
The androgen receptor (AR)-signaling pathways are essential for prostate tumorigenesis. Although significant effort has been devoted to directly targeting AR-expressing tumor cells, these therapies failed in most prostate cancer patients. Here, we demonstrate that loss of AR in stromal sonic-hedgehog Gli1-lineage cells diminishes prostate epithelial oncogenesis and tumor development using in vivo assays and mouse models. Single-cell RNA sequencing and other analyses identified a robust increase of insulin-like growth factor (IGF) binding protein 3 expression in AR-deficient stroma through attenuation of AR suppression on Sp1-regulated transcription, which further inhibits IGF1-induced Wnt/β-catenin activation in adjacent basal epithelial cells and represses their oncogenic growth and tumor development. Epithelial organoids from stromal AR-deficient mice can regain IGF1-induced oncogenic growth. Loss of human prostate tumor basal cell signatures reveals in basal cells of stromal AR-deficient mice. These data demonstrate a distinct mechanism for prostate tumorigenesis and implicate co-targeting stromal and epithelial AR-signaling for prostate cancer.
Identifiants
pubmed: 36323713
doi: 10.1038/s41467-022-34282-w
pii: 10.1038/s41467-022-34282-w
pmc: PMC9630272
doi:
Substances chimiques
Androgens
0
Receptors, Androgen
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
6552Subventions
Organisme : NCI NIH HHS
ID : R01 CA070297
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA166894
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK104941
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA233664
Pays : United States
Informations de copyright
© 2022. The Author(s).
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