Cancer associated fibroblast FAK regulates malignant cell metabolism.
Date
2020-03-10Author
Demircioglu, F
Wang, J
Candido, J
Costa, ASH
Casado, P
de Luxan Delgado, B
Reynolds, LE
Gomez-Escudero, J
Newport, E
Rajeeve, V
Baker, A-M
Roy-Luzarraga, M
Graham, TA
Foster, J
Wang, Y
Campbell, JJ
Singh, R
Zhang, P
Schall, TJ
Balkwill, FR
Sosabowski, J
Cutillas, PR
Frezza, C
Sancho, P
Hodivala-Dilke, K
Type
Journal Article
Metadata
Show full item recordAbstract
Emerging evidence suggests that cancer cell metabolism can be regulated by cancer-associated fibroblasts (CAFs), but the mechanisms are poorly defined. Here we show that CAFs regulate malignant cell metabolism through pathways under the control of FAK. In breast and pancreatic cancer patients we find that low FAK expression, specifically in the stromal compartment, predicts reduced overall survival. In mice, depletion of FAK in a subpopulation of CAFs regulates paracrine signals that increase malignant cell glycolysis and tumour growth. Proteomic and phosphoproteomic analysis in our mouse model identifies metabolic alterations which are reflected at the transcriptomic level in patients with low stromal FAK. Mechanistically we demonstrate that FAK-depletion in CAFs increases chemokine production, which via CCR1/CCR2 on cancer cells, activate protein kinase A, leading to enhanced malignant cell glycolysis. Our data uncover mechanisms whereby stromal fibroblasts regulate cancer cell metabolism independent of genetic mutations in cancer cells.
Collections
Subject
Animals
Breast Neoplasms
Cancer-Associated Fibroblasts
Cell Line, Tumor
Cell Proliferation
Chemokines
Female
Focal Adhesion Protein-Tyrosine Kinases
Glycolysis
Humans
Male
Metabolic Networks and Pathways
Mice, Inbred C57BL
Neoplasms
Pancreatic Neoplasms
Phosphoproteins
Stromal Cells
Survival Analysis
Xenograft Model Antitumor Assays
Research team
Genomics & evolut dynam
Language
eng
Date accepted
2020-02-18
License start date
2020-03-10
Citation
Nature Communications, 2020, 11 (1), pp. 1290 -
Publisher
NATURE PUBLISHING GROUP