User menu

Accès à distance ? S'identifier sur le proxy UCLouvain

Cancer-associated fibroblasts promote prostate cancer malignancy via metabolic rewiring and mitochondrial transfer.

Primary tabs

download
  • Open access
  • PDF
  • 5.62 M
Ippolito, Luigi Morandi, Andrea Taddei, Maria Letizia Parri, Matteo Comito, Giuseppina Muccioli, Giulio [UCL] Sonveaux, Pierre [UCL] Giannoni, Elisa

Cancer-associated fibroblasts (CAFs) are the major cellular stromal component of many solid tumors. In prostate cancer (PCa), CAFs establish a metabolic symbiosis with PCa cells, contributing to cancer aggressiveness through lactate shuttle. In this study, we report that lactate uptake alters the NAD/NADH ratio in the cancer cells, which culminates with SIRT1-dependent PGC-1α activation and subsequent enhancement of mitochondrial mass and activity. The high exploitation of mitochondria results in tricarboxylic acid cycle deregulation, accumulation of oncometabolites and in the altered expression of mitochondrial complexes, responsible for superoxide generation. Additionally, cancer cells hijack CAF-derived functional mitochondria through the formation of cellular bridges, a phenomenon that we observed in both in vitro and in vivo PCa models. Our work reveals a crucial function of tumor mitochondria as the energy sensors and transducers of CAF-dependent metabolic reprogramming and underscores the reliance of PCa cells on CAF catabolic activity and mitochondria trading.

Document type Article de périodique (Journal article)
Access type Accès libre
Publication date 2019
Language Anglais
Journal information "Oncogene" - Vol. 38, no. 27, p. 5339-5355 (2019)
Peer reviewed yes
e-issn 1476-5594
Publication status Accepté/Sous presse
Affiliations UCL - SSS/IREC - Institut de recherche expérimentale et clinique
UCL - SSS/IREC/FATH - Pôle de Pharmacologie et thérapeutique
UCL - SSH/IACS - Institute of Analysis of Change in Contemporary and Historical Societies
Links
  1. Brauer H. A., Makowski L., Hoadley K. A., Casbas-Hernandez P., Lang L. J., Roman-Perez E., D'Arcy M., Freemerman A. J., Perou C. M., Troester M. A., Impact of Tumor Microenvironment and Epithelial Phenotypes on Metabolism in Breast Cancer, 10.1158/1078-0432.ccr-12-2123
  2. Fiaschi T., Marini A., Giannoni E., Taddei M. L., Gandellini P., De Donatis A., Lanciotti M., Serni S., Cirri P., Chiarugi P., Reciprocal Metabolic Reprogramming through Lactate Shuttle Coordinately Influences Tumor-Stroma Interplay, 10.1158/0008-5472.can-12-1949
  3. Giannoni Elisa, Taddei Maria Letizia, Morandi Andrea, Comito Giuseppina, Calvani Maura, Bianchini Francesca, Richichi Barbara, Raugei Giovanni, Wong Nicholas, Tang Damu, Chiarugi Paola, Targeting stromal-induced pyruvate kinase M2 nuclear translocation impairs oxphos and prostate cancer metastatic spread, 10.18632/oncotarget.4448
  4. Ippolito Luigi, Marini Alberto, Cavallini Lorenzo, Morandi Andrea, Pietrovito Laura, Pintus Gianfranco, Giannoni Elisa, Schrader Thomas, Puhr Martin, Chiarugi Paola, Taddei Maria Letizia, Metabolic shift toward oxidative phosphorylation in docetaxel resistant prostate cancer cells, 10.18632/oncotarget.11301
  5. Chandel Navdeep S., Evolution of Mitochondria as Signaling Organelles, 10.1016/j.cmet.2015.05.013
  6. Viale Andrea, Pettazzoni Piergiorgio, Lyssiotis Costas A., Ying Haoqiang, Sánchez Nora, Marchesini Matteo, Carugo Alessandro, Green Tessa, Seth Sahil, Giuliani Virginia, Kost-Alimova Maria, Muller Florian, Colla Simona, Nezi Luigi, Genovese Giannicola, Deem Angela K., Kapoor Avnish, Yao Wantong, Brunetto Emanuela, Kang Ya’an, Yuan Min, Asara John M., Wang Y. Alan, Heffernan Timothy P., Kimmelman Alec C., Wang Huamin, Fleming Jason B., Cantley Lewis C., DePinho Ronald A., Draetta Giulio F., Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function, 10.1038/nature13611
  7. Weinberg F., Hamanaka R., Wheaton W. W., Weinberg S., Joseph J., Lopez M., Kalyanaraman B., Mutlu G. M., Budinger G. R. S., Chandel N. S., Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity, 10.1073/pnas.1003428107
  8. LeBleu Valerie S., O’Connell Joyce T., Gonzalez Herrera Karina N., Wikman Harriet, Pantel Klaus, Haigis Marcia C., de Carvalho Fernanda Machado, Damascena Aline, Domingos Chinen Ludmilla Thome, Rocha Rafael M., Asara John M., Kalluri Raghu, PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis, 10.1038/ncb3039
  9. Torrano Veronica, Valcarcel-Jimenez Lorea, Cortazar Ana Rosa, Liu Xiaojing, Urosevic Jelena, Castillo-Martin Mireia, Fernández-Ruiz Sonia, Morciano Giampaolo, Caro-Maldonado Alfredo, Guiu Marc, Zúñiga-García Patricia, Graupera Mariona, Bellmunt Anna, Pandya Pahini, Lorente Mar, Martín-Martín Natalia, Sutherland James David, Sanchez-Mosquera Pilar, Bozal-Basterra Laura, Zabala-Letona Amaia, Arruabarrena-Aristorena Amaia, Berenguer Antonio, Embade Nieves, Ugalde-Olano Aitziber, Lacasa-Viscasillas Isabel, Loizaga-Iriarte Ana, Unda-Urzaiz Miguel, Schultz Nikolaus, Aransay Ana Maria, Sanz-Moreno Victoria, Barrio Rosa, Velasco Guillermo, Pinton Paolo, Cordon-Cardo Carlos, Locasale Jason W., Gomis Roger R., Carracedo Arkaitz, The metabolic co-regulator PGC1α suppresses prostate cancer metastasis, 10.1038/ncb3357
  10. Tan An S., Baty James W., Dong Lan-Feng, Bezawork-Geleta Ayenachew, Endaya Berwini, Goodwin Jacob, Bajzikova Martina, Kovarova Jaromira, Peterka Martin, Yan Bing, Pesdar Elham Alizadeh, Sobol Margarita, Filimonenko Anatolyj, Stuart Shani, Vondrusova Magdalena, Kluckova Katarina, Sachaphibulkij Karishma, Rohlena Jakub, Hozak Pavel, Truksa Jaroslav, Eccles David, Haupt Larisa M., Griffiths Lyn R., Neuzil Jiri, Berridge Michael V., Mitochondrial Genome Acquisition Restores Respiratory Function and Tumorigenic Potential of Cancer Cells without Mitochondrial DNA, 10.1016/j.cmet.2014.12.003
  11. Dong Lan-Feng, Kovarova Jaromira, Bajzikova Martina, Bezawork-Geleta Ayenachew, Svec David, Endaya Berwini, Sachaphibulkij Karishma, Coelho Ana R, Sebkova Natasa, Ruzickova Anna, Tan An S, Kluckova Katarina, Judasova Kristyna, Zamecnikova Katerina, Rychtarcikova Zuzana, Gopalan Vinod, Andera Ladislav, Sobol Margarita, Yan Bing, Pattnaik Bijay, Bhatraju Naveen, Truksa Jaroslav, Stopka Pavel, Hozak Pavel, Lam Alfred K, Sedlacek Radislav, Oliveira Paulo J, Kubista Mikael, Agrawal Anurag, Dvorakova-Hortova Katerina, Rohlena Jakub, Berridge Michael V, Neuzil Jiri, Horizontal transfer of whole mitochondria restores tumorigenic potential in mitochondrial DNA-deficient cancer cells, 10.7554/elife.22187
  12. Spees J. L., Olson S. D., Whitney M. J., Prockop D. J., Mitochondrial transfer between cells can rescue aerobic respiration, 10.1073/pnas.0510511103
  13. Ishikawa K., Takenaga K., Akimoto M., Koshikawa N., Yamaguchi A., Imanishi H., Nakada K., Honma Y., Hayashi J.-I., ROS-Generating Mitochondrial DNA Mutations Can Regulate Tumor Cell Metastasis, 10.1126/science.1156906
  14. Guarente L., Calorie restriction and sirtuins revisited, 10.1101/gad.227439.113
  15. Houtkooper Riekelt H., Pirinen Eija, Auwerx Johan, Sirtuins as regulators of metabolism and healthspan, 10.1038/nrm3293
  16. Gambini Juan, Gomez-Cabrera Mari Carmen, Borras Consuelo, Valles Soraya L., Lopez-Grueso Raul, Martinez-Bello Vladimir E., Herranz Daniel, Pallardo Federico V., Tresguerres Jesus A.F., Serrano Manuel, Viña Jose, Free [NADH]/[NAD+] regulates sirtuin expression, 10.1016/j.abb.2011.04.020
  17. Rodgers Joseph T., Lerin Carlos, Haas Wilhelm, Gygi Steven P., Spiegelman Bruce M., Puigserver Pere, Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1, 10.1038/nature03354
  18. Nemoto Shino, Fergusson Maria M., Finkel Toren, SIRT1 Functionally Interacts with the Metabolic Regulator and Transcriptional Coactivator PGC-1α, 10.1074/jbc.m501485200
  19. Giannoni Elisa, Bianchini Francesca, Calorini Lido, Chiarugi Paola, Cancer Associated Fibroblasts Exploit Reactive Oxygen Species Through a Proinflammatory Signature Leading to Epithelial Mesenchymal Transition and Stemness, 10.1089/ars.2010.3727
  20. Selak Mary A., Armour Sean M., MacKenzie Elaine D., Boulahbel Houda, Watson David G., Mansfield Kyle D., Pan Yi, Simon M.Celeste, Thompson Craig B., Gottlieb Eyal, Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase, 10.1016/j.ccr.2004.11.022
  21. MacKenzie E. D., Selak M. A., Tennant D. A., Payne L. J., Crosby S., Frederiksen C. M., Watson D. G., Gottlieb E., Cell-Permeating  -Ketoglutarate Derivatives Alleviate Pseudohypoxia in Succinate Dehydrogenase-Deficient Cells, 10.1128/mcb.01927-06
  22. Weinberg Frank, Chandel Navdeep S., Mitochondrial Metabolism and Cancer, 10.1111/j.1749-6632.2009.05039.x
  23. Cannito Stefania, Novo Erica, di Bonzo Lorenzo Valfrè, Busletta Chiara, Colombatto Sebastiano, Parola Maurizio, Epithelial–Mesenchymal Transition: From Molecular Mechanisms, Redox Regulation to Implications in Human Health and Disease, 10.1089/ars.2009.2737
  24. Porporato Paolo E., Payen Valéry L., Pérez-Escuredo Jhudit, De Saedeleer Christophe J., Danhier Pierre, Copetti Tamara, Dhup Suveera, Tardy Morgane, Vazeille Thibaut, Bouzin Caroline, Feron Olivier, Michiels Carine, Gallez Bernard, Sonveaux Pierre, A Mitochondrial Switch Promotes Tumor Metastasis, 10.1016/j.celrep.2014.06.043
  25. Dikalova Anna E., Bikineyeva Alfiya T., Budzyn Klaudia, Nazarewicz Rafal R., McCann Louise, Lewis William, Harrison David G., Dikalov Sergey I., Therapeutic Targeting of Mitochondrial Superoxide in Hypertension, 10.1161/circresaha.109.214601
  26. Nazarewicz Rafal R., Dikalova Anna, Bikineyeva Alfiya, Ivanov Sergey, Kirilyuk Igor A., Grigor'ev Igor A., Dikalov Sergey I., Does Scavenging of Mitochondrial Superoxide Attenuate Cancer Prosurvival Signaling Pathways?, 10.1089/ars.2013.5185
  27. Porporato Paolo E, Sonveaux Pierre, Paving the way for therapeutic prevention of tumor metastasis with agents targeting mitochondrial superoxide, 10.4161/23723548.2014.968043
  28. Giannoni E., Buricchi F., Raugei G., Ramponi G., Chiarugi P., Intracellular Reactive Oxygen Species Activate Src Tyrosine Kinase during Cell Adhesion and Anchorage-Dependent Cell Growth, 10.1128/mcb.25.15.6391-6403.2005
  29. Rogers Robert S., Bhattacharya Jahar, When Cells Become Organelle Donors, 10.1152/physiol.00032.2013
  30. Rustom A., Nanotubular Highways for Intercellular Organelle Transport, 10.1126/science.1093133
  31. Lou Emil, Fujisawa Sho, Morozov Alexei, Barlas Afsar, Romin Yevgeniy, Dogan Yildirim, Gholami Sepideh, Moreira André L., Manova-Todorova Katia, Moore Malcolm A. S., Tunneling Nanotubes Provide a Unique Conduit for Intercellular Transfer of Cellular Contents in Human Malignant Pleural Mesothelioma, 10.1371/journal.pone.0033093
  32. Pasquier Jennifer, Guerrouahen Bella S, Al Thawadi Hamda, Ghiabi Pegah, Maleki Mahtab, Abu-Kaoud Nadine, Jacob Arthur, Mirshahi Massoud, Galas Ludovic, Rafii Shahin, Le Foll Frank, Rafii Arash, Preferential transfer of mitochondria from endothelial to cancer cells through tunneling nanotubes modulates chemoresistance, 10.1186/1479-5876-11-94
  33. Caicedo Andrés, Fritz Vanessa, Brondello Jean-Marc, Ayala Mickaël, Dennemont Indira, Abdellaoui Naoill, de Fraipont Florence, Moisan Anaïck, Prouteau Claire Angebault, Boukhaddaoui Hassan, Jorgensen Christian, Vignais Marie-Luce, MitoCeption as a new tool to assess the effects of mesenchymal stem/stromal cell mitochondria on cancer cell metabolism and function, 10.1038/srep09073
  34. Salem Ahmed F., Whitaker-Menezes Diana, Lin Zhao, Martinez-Outschoorn Ubaldo E., Tanowitz Herbert B., Al-Zoubi Mazhar Salim, Howell Anthony, Pestell Richard G., Sotgia Federica, Lisanti Michael P., Two-compartment tumor metabolism: Autophagy in the tumor microenvironment and oxidative mitochondrial metabolism (OXPHOS) in cancer cells, 10.4161/cc.20920
  35. Morandi Andrea, Giannoni Elisa, Chiarugi Paola, Nutrient Exploitation within the Tumor–Stroma Metabolic Crosstalk, 10.1016/j.trecan.2016.11.001
  36. Chen Ying-Jr, Mahieu Nathaniel G, Huang Xiaojing, Singh Manmilan, Crawford Peter A, Johnson Stephen L, Gross Richard W, Schaefer Jacob, Patti Gary J, Lactate metabolism is associated with mammalian mitochondria, 10.1038/nchembio.2172
  37. Chen E. I., Hewel J., Krueger J. S., Tiraby C., Weber M. R., Kralli A., Becker K., Yates J. R., Felding-Habermann B., Adaptation of Energy Metabolism in Breast Cancer Brain Metastases, 10.1158/0008-5472.can-06-3137
  38. Andrzejewski Sylvia, Klimcakova Eva, Johnson Radia M., Tabariès Sébastien, Annis Matthew G., McGuirk Shawn, Northey Jason J., Chénard Valérie, Sriram Urshila, Papadopoli David J., Siegel Peter M., St-Pierre Julie, PGC-1α Promotes Breast Cancer Metastasis and Confers Bioenergetic Flexibility against Metabolic Drugs, 10.1016/j.cmet.2017.09.006
  39. Kong Xingxing, Wang Rui, Xue Yuan, Liu Xiaojun, Zhang Huabing, Chen Yong, Fang Fude, Chang Yongsheng, Sirtuin 3, a New Target of PGC-1α, Plays an Important Role in the Suppression of ROS and Mitochondrial Biogenesis, 10.1371/journal.pone.0011707
  40. Rabinovitch Rebecca C., Samborska Bozena, Faubert Brandon, Ma Eric H., Gravel Simon-Pierre, Andrzejewski Sylvia, Raissi Thomas C., Pause Arnim, St.-Pierre Julie, Jones Russell G., AMPK Maintains Cellular Metabolic Homeostasis through Regulation of Mitochondrial Reactive Oxygen Species, 10.1016/j.celrep.2017.09.026
  41. Le Gal Kristell, Ibrahim Mohamed X., Wiel Clotilde, Sayin Volkan I., Akula Murali K., Karlsson Christin, Dalin Martin G., Akyürek Levent M., Lindahl Per, Nilsson Jonas, Bergo Martin O., Antioxidants can increase melanoma metastasis in mice, 10.1126/scitranslmed.aad3740
  42. Faubert Brandon, Li Kevin Y., Cai Ling, Hensley Christopher T., Kim Jiyeon, Zacharias Lauren G., Yang Chendong, Do Quyen N., Doucette Sarah, Burguete Daniel, Li Hong, Huet Giselle, Yuan Qing, Wigal Trevor, Butt Yasmeen, Ni Min, Torrealba Jose, Oliver Dwight, Lenkinski Robert E., Malloy Craig R., Wachsmann Jason W., Young Jamey D., Kernstine Kemp, DeBerardinis Ralph J., Lactate Metabolism in Human Lung Tumors, 10.1016/j.cell.2017.09.019
  43. Aspuria Paul-Joseph P, Lunt Sophia Y, Väremo Leif, Vergnes Laurent, Gozo Maricel, Beach Jessica A, Salumbides Brenda, Reue Karen, Wiedemeyer W Ruprecht, Nielsen Jens, Karlan Beth Y, Orsulic Sandra, Succinate dehydrogenase inhibition leads to epithelial-mesenchymal transition and reprogrammed carbon metabolism, 10.1186/2049-3002-2-21
  44. Sciacovelli Marco, Gonçalves Emanuel, Johnson Timothy Isaac, Zecchini Vincent Roberto, da Costa Ana Sofia Henriques, Gaude Edoardo, Drubbel Alizee Vercauteren, Theobald Sebastian Julian, Abbo Sandra Riekje, Tran Maxine Gia Binh, Rajeeve Vinothini, Cardaci Simone, Foster Sarah, Yun Haiyang, Cutillas Pedro, Warren Anne, Gnanapragasam Vincent, Gottlieb Eyal, Franze Kristian, Huntly Brian, Maher Eamonn Richard, Maxwell Patrick Henry, Saez-Rodriguez Julio, Frezza Christian, Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition, 10.1038/nature19353
  45. Martinez-Outschoorn Ubaldo E., Trimmer Casey, Lin Zhao, Whitaker-Menezes Diana, Chiavarina Barbara, Zhou Jie, Wang Chenguang, Pavlides Stephanos, Martinez-Cantarin Maria P., Capozza Franco, Witkiewicz Agnieszka K., Flomenberg Neal, Howell Anthony, Pestell Richard G., Caro Jaime, Lisanti Michael P., Sotgia Federica, Autophagy in cancer associated fibroblasts promotes tumor cell survival : Role of hypoxia, HIF1 induction and NFκB activation in the tumor stromal microenvironment, 10.4161/cc.9.17.12928
  46. Pavlides Stephanos, Whitaker-Menezes Diana, Castello-Cros Remedios, Flomenberg Neal, Witkiewicz Agnieszka K., Frank Philippe G., Casimiro Mathew C., Wang Chenguang, Fortina Paolo, Addya Sankar, Pestell Richard G., Martinez-Outschoorn Ubaldo E., Sotgia Federica, Lisanti Michael P., The reverse Warburg effect: Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma, 10.4161/cc.8.23.10238
  47. Giannoni E., Bianchini F., Masieri L., Serni S., Torre E., Calorini L., Chiarugi P., Reciprocal Activation of Prostate Cancer Cells and Cancer-Associated Fibroblasts Stimulates Epithelial-Mesenchymal Transition and Cancer Stemness, 10.1158/0008-5472.can-10-0785
  48. Santi Alice, Caselli Anna, Ranaldi Francesco, Paoli Paolo, Mugnaioni Camilla, Michelucci Elena, Cirri Paolo, Cancer associated fibroblasts transfer lipids and proteins to cancer cells through cargo vesicles supporting tumor growth, 10.1016/j.bbamcr.2015.09.013
  49. Benton Carley R., Yoshida Yuko, Lally James, Han Xiao-Xia, Hatta Hideo, Bonen Arend, PGC-1α increases skeletal muscle lactate uptake by increasing the expression of MCT1 but not MCT2 or MCT4, 10.1152/physiolgenomics.90217.2008
  50. Summermatter S., Santos G., Perez-Schindler J., Handschin C., Skeletal muscle PGC-1  controls whole-body lactate homeostasis through estrogen-related receptor  -dependent activation of LDH B and repression of LDH A, 10.1073/pnas.1212976110
  51. Pittelli M., Felici R., Pitozzi V., Giovannelli L., Bigagli E., Cialdai F., Romano G., Moroni F., Chiarugi A., Pharmacological Effects of Exogenous NAD on Mitochondrial Bioenergetics, DNA Repair, and Apoptosis, 10.1124/mol.111.073916
  52. Frezza Christian, Cipolat Sara, Scorrano Luca, Organelle isolation: functional mitochondria from mouse liver, muscle and cultured filroblasts, 10.1038/nprot.2006.478
  53. Giannoni E, Fiaschi T, Ramponi G, Chiarugi P, Redox regulation of anoikis resistance of metastatic prostate cancer cells: key role for Src and EGFR-mediated pro-survival signals, 10.1038/onc.2009.77
Bibliographic reference Ippolito, Luigi ; Morandi, Andrea ; Taddei, Maria Letizia ; Parri, Matteo ; Comito, Giuseppina ; et. al. Cancer-associated fibroblasts promote prostate cancer malignancy via metabolic rewiring and mitochondrial transfer.. In: Oncogene, Vol. 38, no. 27, p. 5339-5355 (2019)
Permanent URL http://hdl.handle.net/2078.1/215417