Mutated axon guidance gene PLXNB2 sustains growth and invasiveness of stem cells isolated from cancers of unknown primary.
CUP
EGFR
Plexin
exome
mutation
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
08 03 2023
08 03 2023
Historique:
revised:
28
12
2022
received:
31
03
2022
accepted:
11
01
2023
pubmed:
2
2
2023
medline:
11
3
2023
entrez:
1
2
2023
Statut:
ppublish
Résumé
The genetic changes sustaining the development of cancers of unknown primary (CUP) remain elusive. The whole-exome genomic profiling of 14 rigorously selected CUP samples did not reveal specific recurring mutation in known driver genes. However, by comparing the mutational landscape of CUPs with that of most other human tumor types, it emerged a consistent enrichment of changes in genes belonging to the axon guidance KEGG pathway. In particular, G842C mutation of PlexinB2 (PlxnB2) was predicted to be activating. Indeed, knocking down the mutated, but not the wild-type, PlxnB2 in CUP stem cells resulted in the impairment of self-renewal and proliferation in culture, as well as tumorigenic capacity in mice. Conversely, the genetic transfer of G842C-PlxnB2 was sufficient to promote CUP stem cell proliferation and tumorigenesis in mice. Notably, G842C-PlxnB2 expression in CUP cells was associated with basal EGFR phosphorylation, and EGFR blockade impaired the viability of CUP cells reliant on the mutated receptor. Moreover, the mutated PlxnB2 elicited CUP cell invasiveness, blocked by EGFR inhibitor treatment. In sum, we found that a novel activating mutation of the axon guidance gene PLXNB2 sustains proliferative autonomy and confers invasive properties to stem cells isolated from cancers of unknown primary, in EGFR-dependent manner.
Identifiants
pubmed: 36722641
doi: 10.15252/emmm.202216104
pmc: PMC9994481
doi:
Substances chimiques
ErbB Receptors
EC 2.7.10.1
PLXNB2 protein, human
0
Plxnb2 protein, mouse
0
Nerve Tissue Proteins
0
Banques de données
GEO
['GSE167473']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e16104Informations de copyright
© 2023 The Authors. Published under the terms of the CC BY 4.0 license.
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