[en] Bidirectional interactions between cancer cells and their microenvironment govern tumor progression. Among the stromal cells in this microenvironment, adipocytes have been reported to upregulate cancer cell migration and invasion by producing fatty acids. Conversely, cancer cells alter adipocyte phenotype notably via increased lipolysis. We aimed to identify the mechanisms through which cancer cells trigger adipocyte lipolysis and evaluate the functional consequences on cancer progression. Here, we show that cancer cell-induced acidification of the extracellular medium strongly promotes preadipocyte lipolysis through a mechanism that does not involve lipophagy but requires adipose triglyceride lipase (ATGL) activity. This increased lipolysis is triggered mainly by attenuation of the G0/G1 switch gene 2 (G0S2)-induced inhibition of ATGL. G0S2-mediated regulation in preadipocytes affects their communication with breast cancer cells, modifying the phenotype of the cancer cells and increasing their resistance to chemotherapeutic agents in vitro. Furthermore, we demonstrate that the adipocyte-specific overexpression of G0S2 impairs mammary tumor growth and lung metastasis formation in vivo. Our results highlight the importance of acidosis in cancer cell-adipocyte crosstalk and identify G0S2 as the main regulator of cancer-induced lipolysis, regulating tumor establishment and spreading.
Brohée, Laura; Laboratory of Connective Tissues Biology, GIGA-Cancer, University of Liège, Avenue Hippocrate 13, 4000, Liège, Belgium
Dupont, Laura ; Université de Liège - ULiège > GIGA > GIGA Cancer - Connective Tissue Biology
Lefevre, Camille; Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Avenue Mounier 73, B1.73.11, 1200, Brussels, Belgium
Peiffer, Raphaël ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Saarinen, Alicia M; Department of Biochemistry and Molecular Biology, Mayo Clinic in Arizona Scottsdale, AZ, USA
Peulen, Olivier ; Université de Liège - ULiège > GIGA > GIGA Cancer - Metastases Research Laboratory
Bindels, Laure; Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Avenue Mounier 73, B1.73.11, 1200, Brussels, Belgium
Liu, Jun; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
Colige, Alain ; Université de Liège - ULiège > GIGA > GIGA Cancer - Connective Tissue Biology
Deroanne, Christophe ; Université de Liège - ULiège > GIGA > GIGA Cancer - Connective Tissue Biology
Language :
English
Title :
Acidosis-induced regulation of adipocyte G0S2 promotes crosstalk between adipocytes and breast cancer cells as well as tumor progression.
Roles and regulatory mechanisms of adipocytic lipolysis during tumour progression.
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique ULiège - Université de Liège Fonds Léon Fredericq
Funding number :
7.6507.21
Funding text :
J.C. and C.F.D. were supported by grants from the Léon Frédericq Foundation and the University of Liège, respectively. J.C. is a doctoral fellow from the Televie (7.6507.21). L.D. is a postdoctoral researcher, A.C. is a Senior Research Associate, and C.F.D. is a Research Associate at the Belgian F.R.S.-FNRS.
Hanahan, D., Coussens, L.M., Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21 (2012), 309–322, 10.1016/j.ccr.2012.02.022.
Clement, E., Lazar, I., Muller, C., Nieto, L., Obesity and melanoma: could fat be fueling malignancy?. Pigment Cell Melanoma Res 30 (2017), 294–306, 10.1111/pcmr.12584.
Finley, D.S., Calvert, V.S., Inokuchi, J., Lau, A., Narula, N., Petricoin, E.F., Zaldivar, F., Santos, R., Tyson, D.R., Ornstein, D.K., Periprostatic adipose tissue as a modulator of prostate cancer aggressiveness. J. Urol. 182 (2009), 1621–1627, 10.1016/j.juro.2009.06.015.
Lengyel, E., Makowski, L., DiGiovanni, J., Kolonin, M.G., Cancer as a matter of fat: the crosstalk between adipose tissue and tumors. Trends Cancer 4 (2018), 374–384, 10.1016/j.trecan.2018.03.004.
Nieman, K.M., Kenny, H.A., Penicka, C.V., Ladanyi, A., Buell-Gutbrod, R., Zillhardt, M.R., Romero, I.L., Carey, M.S., Mills, G.B., Hotamisligil, G.S., Yamada, S.D., Peter, M.E., Gwin, K., Lengyel, E., Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat. Med. 17 (2011), 1498–1503, 10.1038/nm.2492.
Attane, C., Muller, C., Drilling for oil: tumor-surrounding adipocytes fueling cancer. Trends Cancer 6 (2020), 593–604, 10.1016/j.trecan.2020.03.001.
Zhang, C., Zhu, N., Li, H., Gong, Y., Gu, J., Shi, Y., Liao, D., Wang, W., Dai, A., Qin, L., New dawn for cancer cell death: emerging role of lipid metabolism. Mol. Metabol., 63, 2022, 101529, 10.1016/j.molmet.2022.101529.
Balaban, S., Shearer, R.F., Lee, L.S., van Geldermalsen, M., Schreuder, M., Shtein, H.C., Cairns, R., Thomas, K.C., Fazakerley, D.J., Grewal, T., Holst, J., Saunders, D.N., Hoy, A.J., Adipocyte lipolysis links obesity to breast cancer growth: adipocyte-derived fatty acids drive breast cancer cell proliferation and migration. Cancer Metabol., 5, 2017, 1, 10.1186/s40170-016-0163-7.
Lehuede, C., Li, X., Dauvillier, S., Vaysse, C., Franchet, C., Clement, E., Esteve, D., Longue, M., Chaltiel, L., Le Gonidec, S., Lazar, I., Geneste, A., Dumontet, C., Valet, P., Nieto, L., Fallone, F., Muller, C., Adipocytes promote breast cancer resistance to chemotherapy, a process amplified by obesity: role of the major vault protein (MVP). Breast Cancer Res., 21, 2019, 7, 10.1186/s13058-018-1088-6.
Wang, Y.Y., Attane, C., Milhas, D., Dirat, B., Dauvillier, S., Guerard, A., Gilhodes, J., Lazar, I., Alet, N., Laurent, V., Le Gonidec, S., Biard, D., Herve, C., Bost, F., Ren, G.S., Bono, F., Escourrou, G., Prentki, M., Nieto, L., Valet, P., Muller, C., Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells. JCI Insight, 2, 2017, e87489, 10.1172/jci.insight.87489.
Yang, A., Mottillo, E.P., Adipocyte lipolysis: from molecular mechanisms of regulation to disease and therapeutics. Biochem. J. 477 (2020), 985–1008, 10.1042/BCJ20190468.
Chen, Y., Yu, C.Y., Deng, W.M., The role of pro-inflammatory cytokines in lipid metabolism of metabolic diseases. Int. Rev. Immunol. 38 (2019), 249–266, 10.1080/08830185.2019.1645138.
Grant, R.W., Stephens, J.M., Fat in flames: influence of cytokines and pattern recognition receptors on adipocyte lipolysis. Am. J. Physiol. Endocrinol. Metab. 309 (2015), E205–E213, 10.1152/ajpendo.00053.2015.
Lyu, X., Zhang, Q., Fares, H.M., Wang, Y., Han, Y., Sun, L., Contribution of adipocytes in the tumor microenvironment to breast cancer metabolism. Cancer Lett., 534, 2022, 215616, 10.1016/j.canlet.2022.215616.
Pillai, S.R., Damaghi, M., Marunaka, Y., Spugnini, E.P., Fais, S., Gillies, R.J., Causes, consequences, and therapy of tumors acidosis. Cancer Metastasis Rev. 38 (2019), 205–222, 10.1007/s10555-019-09792-7.
Pouyssegur, J., Dayan, F., Mazure, N.M., Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441 (2006), 437–443, 10.1038/nature04871.
Lee, S.H., Griffiths, J.R., How and Why Are Cancers Acidic? Carbonic Anhydrase IX and the Homeostatic Control of Tumour Extracellular pH. 2020, Cancers (Basel), 12, 10.3390/cancers12061616.
Riemann, A., Schneider, B., Gundel, D., Stock, C., Gekle, M., Thews, O., Acidosis promotes metastasis formation by enhancing tumor cell motility. Adv. Exp. Med. Biol. 876 (2016), 215–220, 10.1007/978-1-4939-3023-4_27.
Erra Diaz, F., Dantas, E., Geffner, J., Unravelling the interplay between extracellular acidosis and immune cells. Mediat. Inflamm., 2018, 2018, 1218297, 10.1155/2018/1218297.
Klionsky, D.J., et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 12 (2016), 1–222, 10.1080/15548627.2015.1100356 3rd edition.
Rademaker, G., Hennequiere, V., Brohee, L., Nokin, M.J., Lovinfosse, P., Durieux, F., Gofflot, S., Bellier, J., Costanza, B., Herfs, M., Peiffer, R., Bettendorff, L., Deroanne, C., Thiry, M., Delvenne, P., Hustinx, R., Bellahcene, A., Castronovo, V., Peulen, O., Myoferlin controls mitochondrial structure and activity in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness. Oncogene 37 (2018), 4398–4412, 10.1038/s41388-018-0287-z.
Brohee, L., Demine, S., Willems, J., Arnould, T., Colige, A.C., Deroanne, C.F., Lipin-1 regulates cancer cell phenotype and is a potential target to potentiate rapamycin treatment. Oncotarget 6 (2015), 11264–11280, 10.18632/oncotarget.3595.
Heckmann, B.L., Zhang, X., Xie, X., Saarinen, A., Lu, X., Yang, X., Liu, J., Defective adipose lipolysis and altered global energy metabolism in mice with adipose overexpression of the lipolytic inhibitor G0/G1 switch gene 2 (G0S2). J. Biol. Chem. 289 (2014), 1905–1916, 10.1074/jbc.M113.522011.
Hoy, A.J., Balaban, S., Saunders, D.N., Adipocyte-tumor cell metabolic crosstalk in breast cancer. Trends Mol. Med. 23 (2017), 381–392, 10.1016/j.molmed.2017.02.009.
Zhang, S., Peng, X., Yang, S., Li, X., Huang, M., Wei, S., Liu, J., He, G., Zheng, H., Yang, L., Li, H., Fan, Q., The regulation, function, and role of lipophagy, a form of selective autophagy, in metabolic disorders. Cell Death Dis., 13, 2022, 132, 10.1038/s41419-022-04593-3.
Singh, R., Kaushik, S., Wang, Y., Xiang, Y., Novak, I., Komatsu, M., Tanaka, K., Cuervo, A.M., Czaja, M.J., Autophagy regulates lipid metabolism. Nature 458 (2009), 1131–1135, 10.1038/nature07976.
Tzatsos, A., Tsichlis, P.N., Energy depletion inhibits phosphatidylinositol 3-kinase/Akt signaling and induces apoptosis via AMP-activated protein kinase-dependent phosphorylation of IRS-1 at Ser-794. J. Biol. Chem. 282 (2007), 18069–18082, 10.1074/jbc.M610101200.
Menghini, R., Marchetti, V., Cardellini, M., Hribal, M.L., Mauriello, A., Lauro, D., Sbraccia, P., Lauro, R., Federici, M., Phosphorylation of GATA2 by Akt increases adipose tissue differentiation and reduces adipose tissue-related inflammation: a novel pathway linking obesity to atherosclerosis. Circulation 111 (2005), 1946–1953, 10.1161/01.CIR.0000161814.02942.B2.
Tong, Q., Tsai, J., Tan, G., Dalgin, G., Hotamisligil, G.S., Interaction between GATA and the C/EBP family of transcription factors is critical in GATA-mediated suppression of adipocyte differentiation. Mol. Cell Biol. 25 (2005), 706–715, 10.1128/MCB.25.2.706-715.2005.
Rosen, E.D., MacDougald, O.A., Adipocyte differentiation from the inside out. Nat. Rev. Mol. Cell Biol. 7 (2006), 885–896, 10.1038/nrm2066.
Zandbergen, F., Mandard, S., Escher, P., Tan, N.S., Patsouris, D., Jatkoe, T., Rojas-Caro, S., Madore, S., Wahli, W., Tafuri, S., Muller, M., Kersten, S., The G0/G1 switch gene 2 is a novel PPAR target gene. Biochem. J. 392 (2005), 313–324, 10.1042/BJ20050636.
Guan, H.P., Ishizuka, T., Chui, P.C., Lehrke, M., Lazar, M.A., Corepressors selectively control the transcriptional activity of PPARgamma in adipocytes. Genes Dev. 19 (2005), 453–461, 10.1101/gad.1263305.
Dirat, B., Bochet, L., Dabek, M., Daviaud, D., Dauvillier, S., Majed, B., Wang, Y.Y., Meulle, A., Salles, B., Le Gonidec, S., Garrido, I., Escourrou, G., Valet, P., Muller, C., Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res. 71 (2011), 2455–2465, 10.1158/0008-5472.CAN-10-3323.
Mukherjee, A., Bilecz, A.J., Lengyel, E., The adipocyte microenvironment and cancer. Cancer Metastasis Rev. 41 (2022), 575–587, 10.1007/s10555-022-10059-x.
Laurent, V., Toulet, A., Attane, C., Milhas, D., Dauvillier, S., Zaidi, F., Clement, E., Cinato, M., Le Gonidec, S., Guerard, A., Lehuede, C., Garandeau, D., Nieto, L., Renaud-Gabardos, E., Prats, A.C., Valet, P., Malavaud, B., Muller, C., Periprostatic adipose tissue favors prostate cancer cell invasion in an obesity-dependent manner: role of oxidative stress. Mol. Cancer Res. 17 (2019), 821–835, 10.1158/1541-7786.MCR-18-0748.
Rauschner, M., Lange, L., Husing, T., Reime, S., Nolze, A., Maschek, M., Thews, O., Riemann, A., Impact of the acidic environment on gene expression and functional parameters of tumors in vitro and in vivo. J. Exp. Clin. Cancer Res., 40, 2021, 10, 10.1186/s13046-020-01815-4.
Andreucci, E., Peppicelli, S., Carta, F., Brisotto, G., Biscontin, E., Ruzzolini, J., Bianchini, F., Biagioni, A., Supuran, C.T., Calorini, L., Carbonic anhydrase IX inhibition affects viability of cancer cells adapted to extracellular acidosis. J. Mol. Med. (Berl.) 95 (2017), 1341–1353, 10.1007/s00109-017-1590-9.
Estrella, V., Chen, T., Lloyd, M., Wojtkowiak, J., Cornnell, H.H., Ibrahim-Hashim, A., Bailey, K., Balagurunathan, Y., Rothberg, J.M., Sloane, B.F., Johnson, J., Gatenby, R.A., Gillies, R.J., Acidity generated by the tumor microenvironment drives local invasion. Cancer Res. 73 (2013), 1524–1535, 10.1158/0008-5472.CAN-12-2796.
Wojtkowiak, J.W., Verduzco, D., Schramm, K.J., Gillies, R.J., Drug resistance and cellular adaptation to tumor acidic pH microenvironment. Mol. Pharm. 8 (2011), 2032–2038, 10.1021/mp200292c.
Avnet, S., Di Pompo, G., Lemma, S., Baldini, N., Cause and effect of microenvironmental acidosis on bone metastases. Cancer Metastasis Rev. 38 (2019), 133–147, 10.1007/s10555-019-09790-9.
Davern, M., Donlon, N.E., O'Connell, F., Gaughan, C., O'Donovan, C., Habash, M., Sheppard, A.D., MacLean, M., Dunne, M.R., Moore, J., Temperley, H., Conroy, M.J., Butler, C., Bhardwaj, A., Ravi, N., Donohoe, C.L., Reynolds, J.V., Lysaght, J., Acidosis Significantly Alters Immune Checkpoint Expression Profiles of T Cells from Oesophageal Adenocarcinoma Patients. 2022, Cancer Immunol Immunother, 10.1007/s00262-022-03228-y.
Yang, X., Lu, X., Lombes, M., Rha, G.B., Chi, Y.I., Guerin, T.M., Smart, E.J., Liu, J., The G(0)/G(1) switch gene 2 regulates adipose lipolysis through association with adipose triglyceride lipase. Cell Metabol. 11 (2010), 194–205, 10.1016/j.cmet.2010.02.003.
Jin, D., Sun, J., Huang, J., He, Y., Yu, A., Yu, X., Yang, Z., TNF-alpha reduces g0s2 expression and stimulates lipolysis through PPAR-gamma inhibition in 3T3-L1 adipocytes. Cytokine 69 (2014), 196–205, 10.1016/j.cyto.2014.06.005.
Heckmann, B.L., Zhang, X., Saarinen, A.M., Liu, J., Regulation of G0/G1 switch gene 2 (G0S2) protein ubiquitination and stability by triglyceride accumulation and ATGL interaction. PLoS One, 11, 2016, e0156742, 10.1371/journal.pone.0156742.
Zhang, X., Heckmann, B.L., Campbell, L.E., Liu, J., G0S2: a small giant controller of lipolysis and adipose-liver fatty acid flux. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1862 (2017), 1146–1154, 10.1016/j.bbalip.2017.06.007.
Madsen, M.S., Siersbaek, R., Boergesen, M., Nielsen, R., Mandrup, S., Peroxisome proliferator-activated receptor gamma and C/EBPalpha synergistically activate key metabolic adipocyte genes by assisted loading. Mol. Cell Biol. 34 (2014), 939–954, 10.1128/MCB.01344-13.
Rohani, N., Hao, L., Alexis, M.S., Joughin, B.A., Krismer, K., Moufarrej, M.N., Soltis, A.R., Lauffenburger, D.A., Yaffe, M.B., Burge, C.B., Bhatia, S.N., Gertler, F.B., Acidification of tumor at stromal boundaries drives transcriptome alterations associated with aggressive phenotypes. Cancer Res. 79 (2019), 1952–1966, 10.1158/0008-5472.CAN-18-1604.
Nieman, K.M., Romero, I.L., Van Houten, B., Lengyel, E., Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochim. Biophys. Acta 1831 (2013), 1533–1541, 10.1016/j.bbalip.2013.02.010.
