Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy
Authors: Guerrino Meneguzzi
Eloise M Grasset
Thomas Bertero
Etienne Boulter
Paul Hofman
Isabelle Bourget
Alexandre Bozec
Chloe C Feral
Cedric Gaggioli
Sabrina Pisano
William M Oldham
Dmitry V Bulavin
Soline Estrach
Floriant Bellvert
Stephen Y Chan
Journal: Cell metabolism (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: YAP/TAZ; carcinoma-associated fibroblast; extracellular matrix; mechanotransduction; metabolic crosstalk
Affiliations: University Côte d'Azur, CNRS UMR7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France. Electronic address: ., Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., University Côte d'Azur, CNRS UMR7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France., University Côte d'Azur, CNRS UMR7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France; University Côte d'Azur, Laboratory of Clinical and Experimental Pathology, Biobank 0033-00025 and FHU OncoAge, Pasteur Hospital, Nice, France., LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France; MetaToul-MetaboHUB, National Infrastructure of Metabolomics and Fluxomics, Toulouse, France., University Côte d'Azur, CNRS UMR7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Centre Antoine Lacassagne, Nice, France., Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA., University Côte d'Azur, CNRS UMR7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France; Face and Neck University Institute Department of Oncologic Surgery, Nice, France.

Abstract:  Dysregulation of extracellular matrix (ECM) deposition and cellular metabolism promotes tumor aggressiveness by sustaining the activity of key growth, invasion, and survival pathways. Yet mechanisms by which biophysical properties of ECM relate to metabolic processes and tumor progression remain undefined. In both cancer cells and carcinoma-associated fibroblasts (CAFs), we found that ECM stiffening mechanoactivates glycolysis and glutamine metabolism and thus coordinates non-essential amino acid flux within the tumor niche. Specifically, we demonstrate a metabolic crosstalk between CAF and cancer cells in which CAF-derived aspartate sustains cancer cell proliferation, while cancer cell-derived glutamate balances the redox state of CAFs to promote ECM remodeling. Collectively, our findings link mechanical stimuli to dysregulated tumor metabolism and thereby highlight a new metabolic network within tumors in which diverse fuel sources are used to promote growth and aggressiveness. Furthermore, this study identifies potential metabolic drug targets for therapeutic development in cancer. 

Retracted: No

PubPeer comments:
 MDA-MB-468 cells have a very high Ki-67 labelling index (at least 80-90% according to the literature: see for example PMID 23125021; PMID 28588725) in the same culture conditions used in this study. How is it possible then that in this paper CAF-conditioned medium increases it to a further 20-25%(Fig. S1T) ? , 
 Fig.4K-I: critical controls are lacking in the ChIP-seq experiments aimed to show YAP binding and regulation of the *GLS1* and *SLC1A3* promoters, for instance binding to an irrelevant (*e.g.* intronic) sequence by the anti-Yap antibody used for IP. Furthermore, no functional evidence for relevance of those potential binding sites in transcriptional regulation of the genes under study is presented. , 
 In this paper it is not clear whether carcinoma-associated fibroblasts used in the different experiments were matched to the cancer type under study and if specific protocols were used to activate them. If there was a mismatch, this may represent an important uncontrolled variable. ,