Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy.
Adaptor Proteins, Signal Transducing
/ metabolism
Animals
Aspartic Acid
/ metabolism
Breast Neoplasms
/ metabolism
Cancer-Associated Fibroblasts
/ metabolism
Carcinoma
/ metabolism
Cell Line
Extracellular Matrix
Female
Glutamic Acid
/ metabolism
Head and Neck Neoplasms
/ metabolism
Humans
Lung Neoplasms
/ metabolism
Mice
Mice, Inbred BALB C
Trans-Activators
/ metabolism
Transcription Factors
/ metabolism
Transcriptional Coactivator with PDZ-Binding Motif Proteins
YAP-Signaling Proteins
YAP/TAZ
carcinoma-associated fibroblast
extracellular matrix
mechanotransduction
metabolic crosstalk
metastasis
stiffness
tumor niche
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
08 01 2019
08 01 2019
Historique:
received:
24
07
2017
revised:
30
05
2018
accepted:
11
09
2018
pubmed:
9
10
2018
medline:
25
2
2020
entrez:
9
10
2018
Statut:
ppublish
Résumé
Dysregulation of extracellular matrix (ECM) deposition and cellular metabolism promotes tumor aggressiveness by sustaining the activity of key growth, invasion, and survival pathways. Yet mechanisms by which biophysical properties of ECM relate to metabolic processes and tumor progression remain undefined. In both cancer cells and carcinoma-associated fibroblasts (CAFs), we found that ECM stiffening mechanoactivates glycolysis and glutamine metabolism and thus coordinates non-essential amino acid flux within the tumor niche. Specifically, we demonstrate a metabolic crosstalk between CAF and cancer cells in which CAF-derived aspartate sustains cancer cell proliferation, while cancer cell-derived glutamate balances the redox state of CAFs to promote ECM remodeling. Collectively, our findings link mechanical stimuli to dysregulated tumor metabolism and thereby highlight a new metabolic network within tumors in which diverse fuel sources are used to promote growth and aggressiveness. Furthermore, this study identifies potential metabolic drug targets for therapeutic development in cancer.
Identifiants
pubmed: 30293773
pii: S1550-4131(18)30577-1
doi: 10.1016/j.cmet.2018.09.012
pmc: PMC6432652
mid: NIHMS1507308
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Trans-Activators
0
Transcription Factors
0
Transcriptional Coactivator with PDZ-Binding Motif Proteins
0
WWTR1 protein, human
0
YAP-Signaling Proteins
0
YAP1 protein, human
0
Aspartic Acid
30KYC7MIAI
Glutamic Acid
3KX376GY7L
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
124-140.e10Subventions
Organisme : NHLBI NIH HHS
ID : K08 HL128802
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL138437
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL122596
Pays : United States
Organisme : NCATS NIH HHS
ID : UH2 TR002073
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL124021
Pays : United States
Informations de copyright
Copyright © 2018 Elsevier Inc. All rights reserved.
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