c-FOS drives reversible basal to squamous cell carcinoma transition.
Animals
Carcinoma, Basal Cell
/ metabolism
Carcinoma, Squamous Cell
/ metabolism
Cell Transdifferentiation
/ drug effects
Chromatin Assembly and Disassembly
Drug Resistance, Neoplasm
/ genetics
Humans
Male
Mice
Mice, Inbred NOD
Mice, SCID
Mucin-1
/ metabolism
Protein Kinase Inhibitors
/ pharmacology
Proto-Oncogene Proteins c-fos
/ antagonists & inhibitors
RNA Interference
RNA, Small Interfering
/ metabolism
Signal Transduction
/ drug effects
Transcription Factor AP-1
/ metabolism
Transforming Growth Factor beta
/ antagonists & inhibitors
ras Proteins
/ genetics
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
05 10 2021
05 10 2021
Historique:
received:
22
03
2021
revised:
28
06
2021
accepted:
08
09
2021
entrez:
5
10
2021
pubmed:
6
10
2021
medline:
17
2
2022
Statut:
ppublish
Résumé
While squamous transdifferentiation within subpopulations of adenocarcinomas represents an important drug resistance problem, its underlying mechanism remains poorly understood. Here, using surface markers of resistant basal cell carcinomas (BCCs) and patient single-cell and bulk transcriptomic data, we uncover the dynamic roadmap of basal to squamous cell carcinoma transition (BST). Experimentally induced BST identifies activator protein 1 (AP-1) family members in regulating tumor plasticity, and we show that c-FOS plays a central role in BST by regulating the accessibility of distinct AP-1 regulatory elements. Remarkably, despite prominent changes in cell morphology and BST marker expression, we show using inducible model systems that c-FOS-mediated BST demonstrates reversibility. Blocking EGFR pathway activation after c-FOS induction partially reverts BST in vitro and prevents BST features in both mouse models and human tumors. Thus, by identifying the molecular basis of BST, our work reveals a therapeutic opportunity targeting plasticity as a mechanism of tumor resistance.
Identifiants
pubmed: 34610301
pii: S2211-1247(21)01228-6
doi: 10.1016/j.celrep.2021.109774
pmc: PMC8515919
mid: NIHMS1746304
pii:
doi:
Substances chimiques
MUC1 protein, human
0
Mucin-1
0
Protein Kinase Inhibitors
0
Proto-Oncogene Proteins c-fos
0
RNA, Small Interfering
0
Transcription Factor AP-1
0
Transforming Growth Factor beta
0
ras Proteins
EC 3.6.5.2
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
109774Subventions
Organisme : NCI NIH HHS
ID : F32 CA254434
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR046786
Pays : United States
Organisme : NIAMS NIH HHS
ID : R37 AR054780
Pays : United States
Organisme : NIH HHS
ID : S10 OD010580
Pays : United States
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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