The myogenesis program drives clonal selection and drug resistance in rhabdomyosarcoma.
cancer recurrence
muscle development
sarcoma
single-cell biology
tumor heterogeneity
Journal
Developmental cell
ISSN: 1878-1551
Titre abrégé: Dev Cell
Pays: United States
ID NLM: 101120028
Informations de publication
Date de publication:
23 05 2022
23 05 2022
Historique:
received:
13
07
2021
revised:
07
02
2022
accepted:
01
04
2022
pubmed:
29
4
2022
medline:
27
5
2022
entrez:
28
4
2022
Statut:
ppublish
Résumé
Rhabdomyosarcoma (RMS) is a pediatric cancer with features of skeletal muscle; patients with unresectable or metastatic RMS fare poorly due to high rates of disease recurrence. Here, we use single-cell and single-nucleus RNA sequencing to show that RMS tumors recapitulate the spectrum of embryonal myogenesis. Using matched patient samples from a clinical trial and orthotopic patient-derived xenografts (O-PDXs), we show that chemotherapy eliminates the most proliferative component with features of myoblasts within embryonal RMS; after treatment, the immature population with features of paraxial mesoderm expands to reconstitute the developmental hierarchy of the original tumor. We discovered that this paraxial mesoderm population is dependent on EGFR signaling and is sensitive to EGFR inhibitors. Taken together, these data serve as a proof of concept that targeting each developmental state in embryonal RMS is an effective strategy for improving outcomes by preventing disease recurrence.
Identifiants
pubmed: 35483358
pii: S1534-5807(22)00243-X
doi: 10.1016/j.devcel.2022.04.003
pmc: PMC9133224
mid: NIHMS1800632
pii:
doi:
Substances chimiques
ErbB Receptors
EC 2.7.10.1
Banques de données
ClinicalTrials.gov
['NCT01871766']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1226-1240.e8Subventions
Organisme : NCI NIH HHS
ID : R01 CA219686
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA262790
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA021765
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA263969
Pays : United States
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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