Cancer associated fibroblast FAK regulates malignant cell metabolism

Fevzi Demircioglu, Jun Wang, Juliana Candido, Ana S. H. Costa, Pedro Casado, Beatriz Luxan Delgado, Louise E. Reynolds, Jesus Gomez-Escudero, Emma Newport, Vinothini Rajeeve, Ann-Marie Baker, Marina Roy-Luzarraga, Trevor A. Graham, Julie Foster, Yu Wang, James J. Campbell, Rajinder Singh, Penglie Zhang, Thomas J. Schall, Frances R. Balkwill, Jane Sosabowski, Pedro R. Cutillas, Christian Frezza, Patricia Sancho and Kairbaan Hodivala-Dilke ()
Additional contact information
Fevzi Demircioglu: John Vane Science Centre
Jun Wang: John Vane Science Centre
Juliana Candido: John Vane Science Centre
Ana S. H. Costa: Hutchison/MRC Research Centre
Pedro Casado: John Vane Science Centre
Beatriz Luxan Delgado: John Vane Science Centre
Louise E. Reynolds: John Vane Science Centre
Jesus Gomez-Escudero: John Vane Science Centre
Emma Newport: John Vane Science Centre
Vinothini Rajeeve: John Vane Science Centre
Ann-Marie Baker: John Vane Science Centre
Marina Roy-Luzarraga: John Vane Science Centre
Trevor A. Graham: John Vane Science Centre
Julie Foster: John Vane Science Centre
Yu Wang: ChemoCentryx Inc.
James J. Campbell: ChemoCentryx Inc.
Rajinder Singh: ChemoCentryx Inc.
Penglie Zhang: ChemoCentryx Inc.
Thomas J. Schall: ChemoCentryx Inc.
Frances R. Balkwill: John Vane Science Centre
Jane Sosabowski: John Vane Science Centre
Pedro R. Cutillas: John Vane Science Centre
Christian Frezza: Hutchison/MRC Research Centre
Patricia Sancho: John Vane Science Centre
Kairbaan Hodivala-Dilke: John Vane Science Centre

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15104-3

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