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Cancer associated fibroblast FAK regulates malignant cell metabolism.

Published version
Peer-reviewed

Type

Article

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Authors

Demircioglu, Fevzi 
Candido, Juliana 

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.

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Keywords

Journal Title

Nature communications

Conference Name

Journal ISSN

2041-1723

Volume Title

11

Publisher

Sponsorship
Worldwide Cancer Research (16-0390, 16-0390 2016)
Medical Research Council (MC_UU_12022/6)
Biotechnology and Biological Sciences Research Council (BB/M006174/1)
Cancer Research UK (C8218/A21453)
Wellcome Trust (202778/Z/16/Z)