Breast tumor stiffness instructs bone metastasis via maintenance of mechanical conditioning.
Biomechanical Phenomena
Bone Marrow
/ pathology
Bone Neoplasms
/ secondary
Breast Neoplasms
/ pathology
Cell Line, Tumor
Cell Nucleus
/ metabolism
Core Binding Factor Alpha 1 Subunit
/ metabolism
Extracellular Matrix
/ metabolism
Female
Humans
Mechanotransduction, Cellular
Neoplasm Invasiveness
Tumor Microenvironment
ATACseq
RUNX2
biomechanics
bone metastasis
breast cancer
matrix stiffness
mechanical memory
osteolysis
phenotypic plasticity
tumor microenvironment
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
29 06 2021
29 06 2021
Historique:
received:
09
09
2020
revised:
26
02
2021
accepted:
03
06
2021
entrez:
30
6
2021
pubmed:
1
7
2021
medline:
11
2
2022
Statut:
ppublish
Résumé
While the immediate and transitory response of breast cancer cells to pathological stiffness in their native microenvironment has been well explored, it remains unclear how stiffness-induced phenotypes are maintained over time after cancer cell dissemination in vivo. Here, we show that fibrotic-like matrix stiffness promotes distinct metastatic phenotypes in cancer cells, which are preserved after transition to softer microenvironments, such as bone marrow. Using differential gene expression analysis of stiffness-responsive breast cancer cells, we establish a multigenic score of mechanical conditioning (MeCo) and find that it is associated with bone metastasis in patients with breast cancer. The maintenance of mechanical conditioning is regulated by RUNX2, an osteogenic transcription factor, established driver of bone metastasis, and mitotic bookmarker that preserves chromatin accessibility at target gene loci. Using genetic and functional approaches, we demonstrate that mechanical conditioning maintenance can be simulated, repressed, or extended, with corresponding changes in bone metastatic potential.
Identifiants
pubmed: 34192535
pii: S2211-1247(21)00664-1
doi: 10.1016/j.celrep.2021.109293
pmc: PMC8312405
mid: NIHMS1720098
pii:
doi:
Substances chimiques
Core Binding Factor Alpha 1 Subunit
0
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
109293Subventions
Organisme : NCI NIH HHS
ID : P30 CA023074
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL147187
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES006694
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI116629
Pays : United States
Organisme : NHLBI NIH HHS
ID : R00 HL123485
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007249
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA196885
Pays : United States
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests A.W.W. and G.M. have equity in MeCo Diagnostics LLC, which is commercializing the MeCo score under license from the Arizona Board of Regents. G.M. has disclosed an outside interest in MeCo Diagnostics LLC to the University of Arizona. Conflicts of interest resulting from this are being managed by the University of Arizona in accordance with its policies. All of the other authors declare no competing interests.
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