Cancer associated fibroblast FAK regulates malignant cell metabolism.

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ICR Authors

Baker, Ann-Marie Clare
 Graham, Trevor

Authors

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

Document Type

Journal Article

Date

2020-03-10

Date Accepted

2020-02-18

Abstract

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.

Citation

Nature Communications, 2020, 11 (1), pp. 1290 -

DOI

10.1038/s41467-020-15104-3

URI

https://repository.icr.ac.uk/handle/internal/5451

Rights

http://creativecommons.org/licenses/by/4.0/

Source Title

Nature Communications

Publisher

NATURE PUBLISHING GROUP

ISSN

2041-1723

eISSN

2041-1723
2041-1723
2041-1723
2041-1723

Collections

Molecular Pathology

Research Team

Genomics & evolut dynam

Notes