Cancer associated fibroblast FAK regulates malignant cell metabolism.

Nature Communications
Fevzi DemirciogluKairbaan Hodivala-Dilke

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.

References

Jan 28, 1993·Nature·M J Berridge
Apr 30, 2002·Trends in Cell Biology·Johan Van LintThomas Seufferlein
Mar 18, 2003·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·Hisayuki NomiyamaKatsuyuki Hashimoto
Aug 2, 2003·Genes & Development·Deborah BranchoRoger J Davis
Jan 7, 2004·Nature Reviews. Cancer·Jeffrey W Pollard
Mar 16, 2004·Proceedings of the National Academy of Sciences of the United States of America·Jean-Philippe BrunetJill P Mesirov
Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
Jan 21, 2006·World Journal of Surgery·Kenichiro FuruyamaKoji Fujimoto
Feb 16, 2006·The Journal of Biological Chemistry·Sebastien TaurinNickolai O Dulin
Jul 15, 2006·Cell·Karim BensaadKaren H Vousden
Dec 22, 2006·Bioinformatics·Isabelle RivalsMarie-Claude Potier
Feb 5, 2008·Cancer Research·Anthony J TrimboliGustavo Leone
Apr 9, 2008·The Journal of Cell Biology·Sara M WeisDavid A Cheresh
Apr 29, 2008·Nature Medicine·Greg FinakMorag Park
Feb 20, 2009·British Journal of Pharmacology·Sandra Siehler
Mar 20, 2009·Nature Cell Biology·Yongzhan NieQian Gao
Oct 23, 2009·Nature·Anthony J TrimboliGustavo Leone
Dec 15, 2010·EMBO Molecular Medicine·Bernardo TavoraKairbaan M Hodivala-Dilke
Apr 7, 2011·European Journal of Immunology·Carl F FortinPatrick P McDonald
Jun 8, 2011·The Biochemical Journal·F Donelson SmithJohn D Scott
Oct 11, 2011·Nature Reviews. Immunology·Chao Shi, Eric G Pamer
Dec 14, 2011·Nature Medicine·Victor W WongGeoffrey C Gurtner
May 5, 2012·Cancer Research·Jung-whan KimRandall S Johnson
Feb 5, 2013·Bioorganic & Medicinal Chemistry Letters·Andrew M K PennellPenglie Zhang
Jun 5, 2013·Neoplasia : an International Journal for Oncology Research·Mathieu Paul RoderoChristophe Combadière
Jul 20, 2014·Trends in Biochemical Sciences·Krushna C Patra, Nissim Hay
Aug 1, 2014·Nature·Bernardo TavoraKairbaan M Hodivala-Dilke
Aug 8, 2014·Nature Reviews. Cancer·Florian J SulzmaierDavid D Schlaepfer
Oct 2, 2014·Nature Communications·Silvia BatistaKairbaan Hodivala-Dilke
Jan 22, 2015·Nucleic Acids Research·Matthew E RitchieGordon K Smyth
Jun 10, 2015·The Journal of Experimental Medicine·Takanori KitamuraJeffrey W Pollard
Jun 11, 2015·Proceedings of the National Academy of Sciences of the United States of America·Edmund H WilkesPedro Rodriguez Cutillas

❮ Previous
Next ❯

Citations

Sep 6, 2020·Journal of Cellular and Molecular Medicine·Patric TeodorescuCiprian Tomuleasa
Nov 27, 2020·British Journal of Cancer·Luke BoulterValerie G Brunton
Feb 11, 2021·Cancers·Damiano Cosimo RigiraccioloRosamaria Lappano
Feb 13, 2021·Cancers·Pinelopi A NikolopoulouVassiliki Kostourou
Feb 17, 2021·Nature Reviews. Cancer·Thomas R Cox
Feb 13, 2021·Nature Medicine·Ilio VitaleLorenzo Galluzzi
Mar 19, 2021·Nature Reviews. Cancer·John C DawsonMargaret C Frame
Apr 4, 2021·Cancers·Rushikesh S JoshiManish K Aghi
Apr 29, 2021·Nature Reviews. Cancer·Mansi SaxenaNina Bhardwaj
Jan 29, 2021·Cancer Discovery·Prasenjit DeyRonald A DePinho
Jun 5, 2021·Journal of Cell Communication and Signaling·Arun J Singh, Joe W Gray
Jun 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yanting SunChunyan Dong
Jul 3, 2021·Cancers·Mark A EckertErnst Lengyel
Jul 10, 2021·Nature Reviews. Cancer·Samuel A Vilchez MercedesPak Kin Wong
Aug 4, 2021·Trends in Endocrinology and Metabolism : TEM·Yi LiuShuang Tang

❮ Previous
Next ❯

Datasets Mentioned

BETA
PXD008276

Methods Mentioned

BETA
dissection
profiler
GTPases
GTPase
transgenic
flow cytometry
transfection
PCR

Software Mentioned

Kinase Substrate Enrichment Analysis ( KSEA )
ParaVision Acquisition
Cytoscape
KSEA
R
VivoQuant
ImageJ
limma
StepOne Real Time PCR machine
BD FACSDIVA

Related Concepts

Related Feeds

Cancer Metabolic Reprogramming

Cancer metabolic reprogramming is important for the rapid growth and proliferation of cancer cells. Cancer cells have the ability to change their metabolic demands depending on their environment, regulated by the activation of oncogenes or loss of tumor suppressor genes. Here is the latest research on cancer metabolic reprogramming.

Cancer Metabolic Reprogramming (Keystone)

Cancer metabolic reprogramming is important for the rapid growth and proliferation of cancer cells. Cancer cells have the ability to change their metabolic demands depending on their environment, regulated by the activation of oncogenes or loss of tumor suppressor genes. Here is the latest research on cancer metabolic reprogramming.