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Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy
Open accessAbstract
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.
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Citations
Cites
Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590
Microenvironmental regulation of tumor progression and metastasis
Quail, D. F., & Joyce, J. A. (2013) · Nature Medicine · doi:10.1038/nm.3394 · Cited by 7,994
Role of YAP/TAZ in mechanotransduction
Dupont, S., Morsut, L., Aragona, M., Enzo, E., Giulitti, S., Cordenonsi, M., Zanconato, F., Le Digabel, J., Forcato, M., Bicciato, S., et al. (2011) · Nature · doi:10.1038/nature10137 · Cited by 5,979
The biology and function of fibroblasts in cancer
Kalluri, R. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.73 · Cited by 4,366
Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling
Levental, K. R., Yu, H., Kass, L., Lakins, J. N., Egeblad, M., Erler, J. T., Fong, S. F. T., Csiszar, K., Giaccia, A., Weninger, W., et al. (2009) · Cell · doi:10.1016/j.cell.2009.10.027 · Cited by 4,101
The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation
DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G., & Thompson, C. B. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.002 · Cited by 4,088
Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis
Yang, J., Mani, S. A., Donaher, J. L., Ramaswamy, S., Itzykson, R., Côme, C., Savagner, P., Gitelman, I., Richardson, A. L., & Weinberg, R. A. (2004) · Cell · doi:10.1016/j.cell.2004.06.006 · Cited by 3,917
The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1
Sancak, Y., Peterson, T. R., Shaul, Y. D., Lindquist, R. A., Thoreen, C. C., Bar-Peled, L., & Sabatini, D. M. (2008) · Science · doi:10.1126/science.1157535 · Cited by 2,773
Understanding the Intersections between Metabolism and Cancer Biology
Heiden, M. G. V., & DeBerardinis, R. J. (2017) · Cell · doi:10.1016/j.cell.2016.12.039 · Cited by 2,369
Hippo pathway in organ size control, tissue homeostasis, and cancer
Yu, F.-X., Zhao, B., & Guan, K.-L. (2015) · Cell · doi:10.1016/j.cell.2015.10.044 · Cited by 2,206
The extracellular matrix modulates the hallmarks of cancer
Pickup, M. W., Mouw, J. K., & Weaver, V. M. (2014) · EMBO Reports · doi:10.15252/embr.201439246 · Cited by 2,098
Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells
Commisso, C., Davidson, S. M., Soydaner-Azeloglu, R. G., Parker, S. J., Kamphorst, J. J., Hackett, S., Grabocka, E., Nofal, M., Drebin, J. A., Thompson, C. B., et al. (2013) · Nature · doi:10.1038/nature12138 · Cited by 1,683
Gaggioli, C., Hooper, S., Hidalgo-Carcedo, C., Grosse, R., Marshall, J. F., Harrington, K., & Sahai, E. (2007) · Nature Cell Biology · doi:10.1038/ncb1658 · Cited by 1,589
Self-citationCalvo, F., Ege, N., Grande-Garcia, A., Hooper, S., Jenkins, R. P., Chaudhry, S. I., Harrington, K., Williamson, P., Moeendarbary, E., Charras, G., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2756 · Cited by 1,478
Birsoy, K., Wang, T., Chen, W. W., Freinkman, E., Abu-Remaileh, M., & Sabatini, D. M. (2015) · Cell · doi:10.1016/j.cell.2015.07.016 · Cited by 1,388
Glutamine and cancer: cell biology, physiology, and clinical opportunities
Hensley, C. T., Wasti, A. T., & DeBerardinis, R. J. (2013) · Journal of Clinical Investigation · doi:10.1172/jci69600 · Cited by 1,262
Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells
Sullivan, L. B., Gui, D. Y., Hosios, A. M., Bush, L. N., Freinkman, E., & Vander Heiden, M. G. (2015) · Cell · doi:10.1016/j.cell.2015.07.017 · Cited by 1,173
Metabolic heterogeneity in human lung tumors
Hensley, C. T., Faubert, B., Yuan, Q., Lev-Cohain, N., Jin, E., Kim, J., Jiang, L., Ko, B., Skelton, R., Loudat, L., et al. (2016) · Cell · doi:10.1016/j.cell.2015.12.034 · Cited by 1,138
Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion
Sousa, C. M., Biancur, D. E., Wang, X., Halbrook, C. J., Sherman, M. H., Zhang, L., Kremer, D., Hwang, R. F., Witkiewicz, A. K., Ying, H., et al. (2016) · Nature · doi:10.1038/nature19084 · Cited by 1,122
Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer
Gross, M. I., Demo, S. D., Dennison, J. B., Chen, L., Chernov-Rogan, T., Goyal, B., Janes, J. R., Laidig, G. J., Lewis, E. R., Li, J., et al. (2014) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-13-0870 · Cited by 1,068
Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism
Perera, R. M., Stoykova, S., Nicolay, B. N., Ross, K. N., Fitamant, J., Boukhali, M., Lengrand, J., Deshpande, V., Selig, M. K., Ferrone, C. R., et al. (2015) · Nature · doi:10.1038/nature14587 · Cited by 799
Metabolic control of YAP and TAZ by the mevalonate pathway
Sorrentino, G., Ruggeri, N., Specchia, V., Cordenonsi, M., Mano, M., Dupont, S., Manfrin, A., Ingallina, E., Sommaggio, R., Piazza, S., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb2936 · Cited by 776
mTORC1 signaling and the metabolic control of cell growth
Ben‐Sahra, I., & Manning, B. D. (2017) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2017.02.012 · Cited by 668
Spatial organization of the extracellular matrix regulates cell–cell junction positioning
Tseng, Q., Duchemin-Pelletier, E., Deshière, A., Balland, M., Guillou, H., Filhol, O., & Théry, M. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1106377109 · Cited by 611
Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway
Mo, J.-S., Meng, Z., Kim, Y. C., Park, H. W., Hansen, C. G., Kim, S., Lim, D.-S., & Guan, K.-L. (2015) · Nature Cell Biology · doi:10.1038/ncb3111 · Cited by 557
AMPK modulates Hippo pathway activity to regulate energy homeostasis
Wang, W., Xiao, Z.-D., Li, X., Aziz, K. E., Gan, B., Johnson, R. L., & Chen, J. (2015) · Nature Cell Biology · doi:10.1038/ncb3113 · Cited by 549
Emerging patterns of somatic mutations in cancer
Watson, I. R., Takahashi, K., Futreal, P. A., & Chin, L. (2013) · Nature Reviews Genetics · doi:10.1038/nrg3539 · Cited by 497
Metabolism of stromal and immune cells in health and disease
Ghesquière, B., Wong, B. W., Kuchnio, A., & Carmeliet, P. (2014) · Nature · doi:10.1038/nature13312 · Cited by 466
Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours
Garcia-Bermudez, J., Baudrier, L., La, K., Zhu, X. G., Fidelin, J., Sviderskiy, V. O., Papagiannakopoulos, T., Molina, H., Snuderl, M., Lewis, C. A., et al. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0118-z · Cited by 442
Single-vector inducible lentiviral RNAi system for oncology target validation
Wiederschain, D., Susan, W. N., Chen, L., Loo, A. T., Yang, G., Huang, A., Chen, Y., Caponigro, G., Yao, Y.-M., Christoph Lengauer, C., et al. (2009) · Cell Cycle · doi:10.4161/cc.8.3.7701 · Cited by 441
Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension
Bertero, T., Oldham, W. M., Cottrill, K. A., Pisano, S., Vanderpool, R. R., Yu, Q., Zhao, J., Tai, Y., Tang, Y., Zhang, Y.-Y., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci86387 · Cited by 438
Self-citationYang, L., Achreja, A., Yeung, T.-L., Mangala, L. S., Jiang, D., Han, C., Baddour, J., Marini, J. C., Ni, J., Nakahara, R., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.10.011 · Cited by 437
Aerobic glycolysis tunes YAP/TAZ transcriptional activity
Enzo, E., Santinon, G., Pocaterra, A., Aragona, M., Bresolin, S., Forcato, M., Grifoni, D., Pession, A., Zanconato, F., Guzzo, G., et al. (2015) · The EMBO Journal · doi:10.15252/embj.201490379 · Cited by 414
Altered metabolite levels in cancer: implications for tumour biology and cancer therapy
Sullivan, L. B., Gui, D. Y., & Heiden, M. G. V. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.85 · Cited by 406
The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrins
Guilluy, C., Swaminathan, V., García‐Mata, R., O’Brien, E. T., Superfine, R., & Burridge, K. (2011) · Nature Cell Biology · doi:10.1038/ncb2254 · Cited by 396
Albrengues, J., Bertero, T., Grasset, E. M., Bonan, S., Maiel, M., Bourget, I., Philippe, C., Herráiz, C., Benamar, S., Croce, O., et al. (2015) · Nature Communications · doi:10.1038/ncomms10204 · Cited by 383
Self-citationOldham, W. M., Clish, C. B., Yang, Y., & Loscalzo, J. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.06.021 · Cited by 364
Self-citationLevy, D., Adamovich, Y., Reuven, N. B., & Shaul, Y. (2008) · Molecular Cell · doi:10.1016/j.molcel.2007.12.022 · Cited by 363
Aspartate is an endogenous metabolic limitation for tumour growth
Sullivan, L. B., Luengo, A., Danai, L. V., Bush, L. N., Diehl, F. F., Hosios, A. M., Lau, A. N., Elmiligy, S., Malstrom, S. E., Lewis, C. A., et al. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0125-0 · Cited by 349
Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors
Davidson, S. M., Jonas, O., Keibler, M. A., Hou, H. W., Luengo, A., Mayers, J. R., Wyckoff, J., Del Rosario, A. M., Whitman, M., Chin, C. R., et al. (2017) · Nature Medicine · doi:10.1038/nm.4256 · Cited by 331
IsoCor: correcting MS data in isotope labeling experiments
Millard, P., Létisse, F., Sokol, S., & Portais, J. (2012) · Bioinformatics · doi:10.1093/bioinformatics/bts127 · Cited by 278
Force Matters: Biomechanical Regulation of Cell Invasion and Migration in Disease
Kai, F., Laklai, H., & Weaver, V. M. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2016.03.007 · Cited by 257
Bertero, T., Cottrill, K. A., Lu, Y., Haeger, C. M., Dieffenbach, P. B., Annis, S., Hale, A., Bhat, B., Kaimal, V., Zhang, Y., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.09.049 · Cited by 232
Self-citationLIF Mediates Proinvasive Activation of Stromal Fibroblasts in Cancer
Albrengues, J., Bourget, I., Pons, C., Butet, V., Hofman, P. M., Tartare‐Deckert, S., Féral, C. C., Meneguzzi, G., & Gaggioli, C. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.04.036 · Cited by 225
Self-citationLinking E-cadherin mechanotransduction to cell metabolism through force-mediated activation of AMPK
Bays, J., Campbell, H., Heidema, C., Sebbagh, M., & DeMali, K. A. (2017) · Nature Cell Biology · doi:10.1038/ncb3537 · Cited by 221
Bays, J., Peng, X. L., Tolbert, C. E., Guilluy, C., Angell, A. E., Pan, Y., Superfine, R., Burridge, K., & DeMali, K. A. (2014) · The Journal of Cell Biology · doi:10.1083/jcb.201309092 · Cited by 172
Mechano-therapeutics: Targeting Mechanical Signaling in Fibrosis and Tumor Stroma
Tschumperlin, D. J., & Lagares, D. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107575 · Cited by 146
Role of the mechanical microenvironment in cancer development and progression
Liu, Q., Luo, Q., Ju, Y., & Song, G. (2020) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2019.0437 · Cited by 123
Regulation of the Hippo pathway and implications for anticancer drug development
Park, H. W., & Guan, K. (2013) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2013.08.006 · Cited by 119
A Potential Role of YAP/TAZ in the Interplay Between Metastasis and Metabolic Alterations
Yamaguchi, H., & Taouk, G. M. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00928 · Cited by 106
Glutamine‐utilizing transaminases are a metabolic vulnerability of TAZ/YAP‐activated cancer cells
Yang, C., Stampouloglou, E., Kingston, N. M., Zhang, L., Monti, S., & Varelas, X. (2018) · EMBO Reports · doi:10.15252/embr.201643577 · Cited by 97
dNTP metabolism links mechanical cues and YAP/TAZ to cell growth and oncogene‐induced senescence
Santinon, G., Brian, I., Pocaterra, A., Romani, P., Franzolin, E., Rampazzo, C., Bicciato, S., & Dupont, S. (2018) · The EMBO Journal · doi:10.15252/embj.201797780 · Cited by 93
Liu, F., Haeger, C. M., Dieffenbach, P. B., Sicard, D., Chrobak, I., Coronata, A. M. F., Velandia, M. M. S., Vitali, S. H., Colas, R. A., Norris, P. C., et al. (2016) · JCI Insight · doi:10.1172/jci.insight.86987 · Cited by 74
Bertero, T., Cottrill, K. A., Annis, S., Bhat, B., Gochuico, B. R., Osorio, J. C., Rosas, I. O., Haley, K. J., Corey, K. E., Chung, R. T., et al. (2015) · Scientific Reports · doi:10.1038/srep18277 · Cited by 67
Self-citationNutritional Exchanges Within Tumor Microenvironment: Impact for Cancer Aggressiveness
Comito, G., Ippolito, L., Chiarugi, P., & Cirri, P. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00396 · Cited by 60
Heuillet, M., Bellvert, F., Cahoreau, E., Létisse, F., Millard, P., & Portais, J. (2017) · Analytical Chemistry · doi:10.1021/acs.analchem.7b03886 · Cited by 47
Self-citationImmunoscore Predicts Survival in Early-Stage Lung Adenocarcinoma Patients
Zhao, Z., Zhao, D., Ji, X., Wang, Y., & Wang, B. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00691 · Cited by 24
Analysis of Collective Invasion of Carcinoma Cells in a 3D Organotypic Model
Albrengues, J., Meneguzzi, G., & Gaggioli, C. (2012) · Methods in molecular biology · doi:10.1007/978-1-62703-227-8_15 · Cited by 11
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Metadata
- Authors
- Bertero, T., Oldham, W. M., Grasset, E. M., Bourget, I., Boulter, E., Pisano, S., Hofman, P., Bellvert, F., Meneguzzi, G., Bulavin, D. V., Estrach, S., Feral, C. C., Chan, S. Y., Bozec, A., & Gaggioli, C.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Brigham and Women's Hospital (US)
- University of Pittsburgh Medical Center (US)
- Corresponding author
- Bertero, Thomas
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2019-01
- Volume
- 29
- Issue
- 1
- Pages
- 124-140.e10
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC6432652
- OpenAlex
- W2895250239
- Cited by
- 393
- References
- 56
- Citations by year
- 2026: 45 · 2025: 56 · 2024: 71 · 2023: 56 · 2022: 53 · 2021: 49 · 2020: 39 · 2019: 23
- FWCI
- 8.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, cc-by-nc)
- Funders
- Ligue Contre le Cancer
- Agence Nationale de la Recherche (ANR-11-LABX-0028-01)
- Association pour la Recherche sur le Cancer (PJA20131200325)
- American Heart Association (HL128802, 18EIA33900027)
- Canceropôle PACA
- Fondation pour la Recherche Médicale (DEQ20180339183)
- National Institutes of Health (HL 138437, UH2 TR002073, HL 122596, R01 HL124021)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- extracellular matrix stiffness, mechanotransduction, glycolysis, glutamine metabolism, amino acid availability, cancer-associated fibroblasts, tumor cell proliferation, aspartic acid, glutamate, redox state, extracellular matrix remodeling, cancer metabolism, metabolic crosstalk, cancer drug targets
- MeSH terms
- Cancer-Associated Fibroblasts, YAP-Signaling Proteins, Transcriptional Coactivator with PDZ-Binding Motif Proteins, Animals, Aspartic Acid, Breast Neoplasms, Carcinoma, Cell Line, Extracellular Matrix, Female, Head and Neck Neoplasms, Humans, Lung Neoplasms, Mice, Inbred BALB C, Transcription Factors, Trans-Activators, Glutamic Acid, Adaptor Proteins, Signal Transducing, Mice
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