ASCL1 is activated downstream of the ROR2/CREB signaling pathway to support lineage plasticity in prostate cancer.
Humans
Male
Neoplasm Recurrence, Local
/ drug therapy
Prostatic Neoplasms
/ genetics
Signal Transduction
Transcription Factors
Androgen Receptor Antagonists
/ therapeutic use
Receptors, Androgen
/ metabolism
Cell Line, Tumor
Basic Helix-Loop-Helix Transcription Factors
/ metabolism
Receptor Tyrosine Kinase-like Orphan Receptors
/ genetics
ASCL1
CP: Cancer
CREB
ROR2
cellular plasticity
neuroendocrine
prostate cancer
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
29 08 2023
29 08 2023
Historique:
received:
22
02
2023
revised:
16
07
2023
accepted:
20
07
2023
medline:
4
9
2023
pubmed:
8
8
2023
entrez:
8
8
2023
Statut:
ppublish
Résumé
Lineage plasticity is a form of therapy-induced drug resistance. In prostate cancer, androgen receptor (AR) pathway inhibitors potentially lead to the accretion of tumor relapse with loss of AR signaling and a shift from a luminal state to an alternate program. However, the molecular and signaling mechanisms orchestrating the development of lineage plasticity under the pressure of AR-targeted therapies are not fully understood. Here, a survey of receptor tyrosine kinases (RTKs) identifies ROR2 as the top upregulated RTK following AR pathway inhibition, which feeds into lineage plasticity by promoting stem-cell-like and neuronal networks. Mechanistically, ROR2 activates the ERK/CREB signaling pathway to modulate the expression of the lineage commitment transcription factor ASCL1. Collectively, our findings nominate ROR2 as a potential therapeutic target to reverse the ENZ-induced plastic phenotype and potentially re-sensitize tumors to AR pathway inhibitors.
Identifiants
pubmed: 37552603
pii: S2211-1247(23)00948-8
doi: 10.1016/j.celrep.2023.112937
pii:
doi:
Substances chimiques
Transcription Factors
0
Androgen Receptor Antagonists
0
Receptors, Androgen
0
ASCL1 protein, human
0
Basic Helix-Loop-Helix Transcription Factors
0
ROR2 protein, human
EC 2.7.10.1
Receptor Tyrosine Kinase-like Orphan Receptors
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
112937Subventions
Organisme : CIHR
ID : 169173
Pays : Canada
Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.