Increased Lactate Secretion by Cancer Cells Sustains Non-cell-autonomous Adaptive Resistance to MET and EGFR Targeted Therapies

M. Apicella, E. Giannoni, S. Fiore, K.J. Ferrari, D. Fernández-Pérez, C. Isella, C. Granchi, F. Minutolo, A. Sottile, P.M. Comoglio, E. Medico, F. Pietrantonio, M. Volante, D. Pasini, P. Chiarugi, S. Giordano, S. Corso

Research output: Contribution to journalArticle

Abstract

The tumor microenvironment shapes cancer progression. Apicella et al. now show that cancer-associated fibroblasts play an active metabolic role in adaptive cancer drug resistance to tyrosine kinase inhibitors (TKIs). Targeting the non-cell-autonomous lactate/HGF/MET-signaling axis abrogated acquired TKI resistance in cancer models. © 2018 Elsevier Inc. The microenvironment influences cancer drug response and sustains resistance to therapies targeting receptor-tyrosine kinases. However, if and how the tumor microenvironment can be altered during treatment, contributing to resistance onset, is not known. We show that, under prolonged treatment with tyrosine kinase inhibitors (TKIs), EGFR- or MET-addicted cancer cells displayed a metabolic shift toward increased glycolysis and lactate production. We identified secreted lactate as the key molecule instructing cancer-associated fibroblasts to produce hepatocyte growth factor (HGF) in a nuclear factor κB-dependent manner. Increased HGF, activating MET-dependent signaling in cancer cells, sustained resistance to TKIs. Functional or pharmacological targeting of molecules involved in the lactate axis abrogated in vivo resistance, demonstrating the crucial role of this metabolite in the adaptive process. This adaptive resistance mechanism was observed in lung cancer patients progressed on EGFR TKIs, demonstrating the clinical relevance of our findings and opening novel scenarios in the challenge to drug resistance. © 2018 Elsevier Inc.
Original languageEnglish
Pages (from-to)848
JournalCell Metabolism
Volume28
Issue number6
DOIs
Publication statusPublished - 2018

Fingerprint

Protein-Tyrosine Kinases
Lactic Acid
Tumor Microenvironment
Hepatocyte Growth Factor
Neoplasms
Drug Resistance
Therapeutics
Receptor Protein-Tyrosine Kinases
Glycolysis
Lung Neoplasms
Pharmacology
Pharmaceutical Preparations
Cancer-Associated Fibroblasts

Keywords

  • CAFs
  • EGFR
  • HGF/MET
  • lactate
  • LDH
  • MCT1/4
  • resistance
  • targeted therapy
  • tumor metabolism
  • tumor microenvironment

Cite this

Increased Lactate Secretion by Cancer Cells Sustains Non-cell-autonomous Adaptive Resistance to MET and EGFR Targeted Therapies. / Apicella, M.; Giannoni, E.; Fiore, S.; Ferrari, K.J.; Fernández-Pérez, D.; Isella, C.; Granchi, C.; Minutolo, F.; Sottile, A.; Comoglio, P.M.; Medico, E.; Pietrantonio, F.; Volante, M.; Pasini, D.; Chiarugi, P.; Giordano, S.; Corso, S.

In: Cell Metabolism, Vol. 28, No. 6, 2018, p. 848.

Research output: Contribution to journalArticle

Apicella, M. ; Giannoni, E. ; Fiore, S. ; Ferrari, K.J. ; Fernández-Pérez, D. ; Isella, C. ; Granchi, C. ; Minutolo, F. ; Sottile, A. ; Comoglio, P.M. ; Medico, E. ; Pietrantonio, F. ; Volante, M. ; Pasini, D. ; Chiarugi, P. ; Giordano, S. ; Corso, S. / Increased Lactate Secretion by Cancer Cells Sustains Non-cell-autonomous Adaptive Resistance to MET and EGFR Targeted Therapies. In: Cell Metabolism. 2018 ; Vol. 28, No. 6. pp. 848.
@article{c2706a6f2ec340ca947aa22a9dfb7429,
title = "Increased Lactate Secretion by Cancer Cells Sustains Non-cell-autonomous Adaptive Resistance to MET and EGFR Targeted Therapies",
abstract = "The tumor microenvironment shapes cancer progression. Apicella et al. now show that cancer-associated fibroblasts play an active metabolic role in adaptive cancer drug resistance to tyrosine kinase inhibitors (TKIs). Targeting the non-cell-autonomous lactate/HGF/MET-signaling axis abrogated acquired TKI resistance in cancer models. {\circledC} 2018 Elsevier Inc. The microenvironment influences cancer drug response and sustains resistance to therapies targeting receptor-tyrosine kinases. However, if and how the tumor microenvironment can be altered during treatment, contributing to resistance onset, is not known. We show that, under prolonged treatment with tyrosine kinase inhibitors (TKIs), EGFR- or MET-addicted cancer cells displayed a metabolic shift toward increased glycolysis and lactate production. We identified secreted lactate as the key molecule instructing cancer-associated fibroblasts to produce hepatocyte growth factor (HGF) in a nuclear factor κB-dependent manner. Increased HGF, activating MET-dependent signaling in cancer cells, sustained resistance to TKIs. Functional or pharmacological targeting of molecules involved in the lactate axis abrogated in vivo resistance, demonstrating the crucial role of this metabolite in the adaptive process. This adaptive resistance mechanism was observed in lung cancer patients progressed on EGFR TKIs, demonstrating the clinical relevance of our findings and opening novel scenarios in the challenge to drug resistance. {\circledC} 2018 Elsevier Inc.",
keywords = "CAFs, EGFR, HGF/MET, lactate, LDH, MCT1/4, resistance, targeted therapy, tumor metabolism, tumor microenvironment",
author = "M. Apicella and E. Giannoni and S. Fiore and K.J. Ferrari and D. Fern{\'a}ndez-P{\'e}rez and C. Isella and C. Granchi and F. Minutolo and A. Sottile and P.M. Comoglio and E. Medico and F. Pietrantonio and M. Volante and D. Pasini and P. Chiarugi and S. Giordano and S. Corso",
note = "Cited By :1 Export Date: 5 February 2019 Correspondence Address: Giordano, S.; Candiolo Cancer Institute - FPO, IRCCS, Strada Provinciale 142, Italy; email: silvia.giordano@unito.it Funding details: Associazione Italiana per la Ricerca sul Cancro Funding details: Janssen Biotech Funding details: Fondazione Umberto Veronesi Funding details: Ministero della Salute Funding details: Fondazione Italiana per la Ricerca sul Cancro, FIRC Funding details: Associazione Italiana per la Ricerca sul Cancro, 20210 Funding text 1: We thank all our colleagues for helpful scientific discussion; Barbara Martinoglio and Roberta Porporato for providing technical support with real-time PCR and in situ hybridization; Paola Bernabei for technical support with FACS and sorting experiments; Stefania Giove for support with histological preparations; Francesco Fesi for hematochemical analysis; Alberto Puliafito for RNAscope quantification; employees of the animal facility; Dr. Carlos Sebastian for help with metabolic experiments; Dr. Annalisa Petrelli for support in RNAi experiments; Dr. Natale for critical reading of the manuscript. JNJ-605 was kindly provided by Janssen. This work was funded by the University of Torino , Fondo Ricerca Locale 2013 to S.C.; PROGETTO ATENEO/Compagnia San Paolo 2016, University of Torino to S.C.; the Italian Association for Cancer Research (AIRC), IG grant 20210 to S.G.; Fondazione Piemontese per la Ricerca sul Cancro (ONLUS) 5 X 1000 Fondi Ministero della Salute 2013 to A.S. and 2014 to S.G.; M.A. is a recipient of a Fondazione Veronesi Research Fellowship. References: Allen, E., Mi{\'e}ville, P., Warren, C.M., Saghafinia, S., Li, L., Peng, M.W., Hanahan, D., Metabolic symbiosis enables adaptive resistance to anti-angiogenic therapy that is dependent on mTOR signaling (2016) Cell Rep., 15, pp. 1144-1160; Arbiser, J.L., Raab, G., Rohan, R.M., Paul, S., Hirschi, K., Flynn, E., Price, E.R., Klagsbrun, M., Isolation of mouse stromal cells associated with a human tumor using differential diphtheria toxin sensitivity (1999) Am. J. Pathol., 155, pp. 723-729; Bacci, M., Giannoni, E., Fearns, A., Ribas, R., Gao, Q., Taddei, M.L., Pintus, G., Martin, L.A., miR-155 drives metabolic reprogramming of ER+ breast cancer cells following long-term estrogen deprivation and predicts clinical response to aromatase inhibitors (2016) Cancer Res., 76, pp. 1615-1626; Bhowmick, N.A., Neilson, E.G., Moses, H.L., Stromal fibroblasts in cancer initiation and progression (2004) Nature, 432, pp. 332-337; Bonuccelli, G., Tsirigos, A., Whitaker-Menezes, D., Pavlides, S., Pestell, R.G., Chiavarina, B., Frank, P.G., Martinez-Outschoorn, U.E., Ketones and lactate “fuel” tumor growth and metastasis: evidence that epithelial cancer cells use oxidative mitochondrial metabolism (2010) Cell Cycle, 9, pp. 3506-3514; Bottaro, D.P., Rubin, J.S., Faletto, D.L., Chan, A.M., Kmiecik, T.E., Vande Woude, G.F., Aaronson, S.A., Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product (1991) Science, 251, pp. 802-804; Calvaresi, E.C., Granchi, C., Tuccinardi, T., Di Bussolo, V., Huigens, R.W., Lee, H.Y., Palchaudhuri, R., Minutolo, F., Dual targeting of the Warburg effect with a glucose-conjugated lactate dehydrogenase inhibitor (2013) ChemBioChem, 14, pp. 2263-2267; Camidge, D.R., Pao, W., Sequist, L.V., Acquired resistance to TKIs in solid tumours: learning from lung cancer (2014) Nat. Rev. Clin. Oncol., 11, pp. 473-481; Carbone, C., Moccia, T., Zhu, C., Paradiso, G., Budillon, A., Chiao, P.J., Abbruzzese, J.L., Melisi, D., Anti-VEGF treatment-resistant pancreatic cancers secrete proinflammatory factors that contribute to malignant progression by inducing an EMT cell phenotype (2011) Clin. Cancer Res., 17, pp. 5822-5832; Carrolo, M., Giordano, S., Cabrita-Santos, L., Corso, S., Vig{\'a}rio, A.M., Silva, S., Leiri{\~a}o, P., Comoglio, P.M., Hepatocyte growth factor and its receptor are required for malaria infection (2003) Nat. Med., 9, pp. 1363-1369; Cecchi, F., Lih, C.J., Lee, Y.H., Walsh, W., Rabe, D.C., Williams, P.M., Bottaro, D.P., Expression array analysis of the hepatocyte growth factor invasive program (2015) Clin. Exp. Metastasis, 32, pp. 659-676; Cepero, V., Sierra, J.R., Corso, S., Ghiso, E., Casorzo, L., Perera, T., Comoglio, P.M., Giordano, S., MET and KRAS gene amplification mediates acquired resistance to MET tyrosine kinase inhibitors (2010) Cancer Res., 70, pp. 7580-7590; Chong, C.R., J{\"a}nne, P.A., The quest to overcome resistance to EGFR-targeted therapies in cancer (2013) Nat. Med., 19, pp. 1389-1400; Comoglio, P.M., Trusolino, L., Boccaccio, C., Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy (2018) Nat. Rev. Cancer, 18, pp. 341-358; Corso, S., Ghiso, E., Cepero, V., Sierra, J.R., Migliore, C., Bertotti, A., Trusolino, L., Giordano, S., Activation of HER family members in gastric carcinoma cells mediates resistance to MET inhibition (2010) Mol. Cancer, 9, p. 121; Cross, D.A., Ashton, S.E., Ghiorghiu, S., Eberlein, C., Nebhan, C.A., Spitzler, P.J., Orme, J.P., Mellor, M.J., AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer (2014) Cancer Discov., 4, pp. 1046-1061; Cui, J.J., Targeting receptor tyrosine kinase MET in cancer: small molecule inhibitors and clinical progress (2014) J. Med. Chem., 57, pp. 4427-4453; Curtarello, M., Zulato, E., Nardo, G., Valtorta, S., Guzzo, G., Rossi, E., Esposito, G., Rasola, A., VEGF-targeted therapy stably modulates the glycolytic phenotype of tumor cells (2015) Cancer Res., 75, pp. 120-133; Dillon, R., Nilsson, C.L., Shi, S.D., Lee, N.V., Krastins, B., Greig, M.J., Discovery of a novel B-Raf fusion protein related to c-Met drug resistance (2011) J. Proteome Res., 10, pp. 5084-5094; Engelman, J.A., Settleman, J., Acquired resistance to tyrosine kinase inhibitors during cancer therapy (2008) Curr. Opin. Genet. Dev., 18, pp. 73-79; Fiaschi, T., Marini, A., Giannoni, E., Taddei, M.L., Gandellini, P., De Donatis, A., Lanciotti, M., Chiarugi, P., Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay (2012) Cancer Res., 72, pp. 5130-5140; Gherardi, E., Birchmeier, W., Birchmeier, C., Vande Woude, G., Targeting MET in cancer: rationale and progress (2012) Nat. Rev. Cancer, 12, pp. 89-103; Giordano, S., Ponzetto, C., Di Renzo, M.F., Cooper, C.S., Comoglio, P.M., Tyrosine kinase receptor indistinguishable from the c-met protein (1989) Nature, 339, pp. 155-156; Harbinski, F., Craig, V.J., Sanghavi, S., Jeffery, D., Liu, L., Sheppard, K.A., Wagner, S., Chatenay-Rivauday, C., Rescue screens with secreted proteins reveal compensatory potential of receptor tyrosine kinases in driving cancer growth (2012) Cancer Discov., 2, pp. 948-959; Harrison, P.M., Farzaneh, F., Regulation of HGF/SF gene expression in MRC-5 cells by N-acetylcysteine (2000) Biochem. Biophys. Res. Commun., 279, pp. 108-115; Hata, A.N., Niederst, M.J., Archibald, H.L., Gomez-Caraballo, M., Siddiqui, F.M., Mulvey, H.E., Maruvka, Y.E., Krishnamurthy Radhakrishna, V., Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition (2016) Nat. Med., 22, pp. 262-269; Hu, Y., Yan, C., Mu, L., Huang, K., Li, X., Tao, D., Wu, Y., Qin, J., Fibroblast-derived exosomes contribute to chemoresistance through priming cancer stem cells in colorectal cancer (2015) PLoS One, 10, p. e0125625; Jim{\'e}nez-Valerio, G., Mart{\'i}nez-Lozano, M., Bassani, N., Vidal, A., Ochoa-de-Olza, M., Su{\'a}rez, C., Garc{\'i}a-Del-Muro, X., Graupera, M., Resistance to antiangiogenic therapies by metabolic symbiosis in renal cell carcinoma PDX models and patients (2016) Cell Rep., 15, pp. 1134-1143; Kanno, T., Sudo, K., Maekawa, M., Nishimura, Y., Ukita, M., Fukutake, K., Lactate dehydrogenase M-subunit deficiency: a new type of hereditary exertional myopathy (1988) Clin. Chim. Acta, 173, pp. 89-98; Lai, I.L., Chou, C.C., Lai, P.T., Fang, C.S., Shirley, L.A., Yan, R., Mo, X., Bekaii-Saab, T., Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells (2014) Carcinogenesis, 35, pp. 2203-2213; Lennerz, J.K., Kwak, E.L., Ackerman, A., Michael, M., Fox, S.B., Bergethon, K., Lauwers, G.Y., Haber, D.A., MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib (2011) J. Clin. Oncol., 29, pp. 4803-4810; Lovly, C.M., Shaw, A.T., Molecular pathways: resistance to kinase inhibitors and implications for therapeutic strategies (2014) Clin. Cancer Res., 20, pp. 2249-2256; Maemondo, M., Inoue, A., Kobayashi, K., Sugawara, S., Oizumi, S., Isobe, H., Gemma, A., Kinoshita, I., Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR (2010) N. Engl. J. Med., 362, pp. 2380-2388; Martinez-Outschoorn, U.E., Lisanti, M.P., Sotgia, F., Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth (2014) Semin. Cancer Biol., 25, pp. 47-60; Martinez-Outschoorn, U.E., Peiris-Pag{\'e}s, M., Pestell, R.G., Sotgia, F., Lisanti, M.P., Cancer metabolism: a therapeutic perspective (2017) Nat. Rev. Clin. Oncol., 14, p. 113; Meads, M.B., Gatenby, R.A., Dalton, W.S., Environment-mediated drug resistance: a major contributor to minimal residual disease (2009) Nat. Rev. Cancer, 9, pp. 665-674; Mok, T.S., Wu, Y.L., Ahn, M.J., Garassino, M.C., Kim, H.R., Ramalingam, S.S., Shepherd, F.A., Theelen, W.S., Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer (2017) N. Engl. J. Med., 376, pp. 629-640; Mok, T.S., Wu, Y.L., Thongprasert, S., Yang, C.H., Chu, D.T., Saijo, N., Sunpaweravong, P., Ichinose, Y., Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma (2009) N. Engl. J. Med., 361, pp. 947-957; Moore, M.J., Goldstein, D., Hamm, J., Figer, A., Hecht, J.R., Gallinger, S., Au, H.J., Wolff, R.A., Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group (2007) J. Clin. Oncol., 25, pp. 1960-1966; Ohashi, K., Maruvka, Y.E., Michor, F., Pao, W., Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease (2013) J. Clin. Oncol., 31, pp. 1070-1080; Pasini, D., Malatesta, M., Jung, H.R., Walfridsson, J., Willer, A., Olsson, L., Skotte, J., Jensen, O.N., Characterization of an antagonistic switch between histone H3 lysine 27 methylation and acetylation in the transcriptional regulation of Polycomb group target genes (2010) Nucleic Acids Res., 38, pp. 4958-4969; Pennacchietti, S., Cazzanti, M., Bertotti, A., Rideout, W.M., Han, M., Gyuris, J., Perera, T., Michieli, P., Microenvironment-derived HGF overcomes genetically determined sensitivity to anti-MET drugs (2014) Cancer Res., 74, pp. 6598-6609; Pennacchietti, S., Michieli, P., Galluzzo, M., Mazzone, M., Giordano, S., Comoglio, P.M., Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene (2003) Cancer Cell, 3, pp. 347-361; Peters, S., Adjei, A.A., MET: a promising anticancer therapeutic target (2012) Nat. Rev. Clin. Oncol., 9, pp. 314-326; Pietrantonio, F., Vernieri, C., Siravegna, G., Mennitto, A., Berenato, R., Perrone, F., Gloghini, A., Morano, F., Heterogeneity of acquired resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer (2017) Clin. Cancer Res., 23, pp. 2414-2422; Pisarsky, L., Bill, R., Fagiani, E., Dimeloe, S., Goosen, R.W., Hagmann, J., Hess, C., Christofori, G., Targeting metabolic symbiosis to overcome resistance to anti-angiogenic therapy (2016) Cell Rep., 15, pp. 1161-1174; Puri, N., Salgia, R., Synergism of EGFR and c-Met pathways, cross-talk and inhibition, in non-small cell lung cancer (2008) J. Carcinog., 7, p. 9; Qi, J., McTigue, M.A., Rogers, A., Lifshits, E., Christensen, J.G., J{\"a}nne, P.A., Engelman, J.A., Multiple mutations and bypass mechanisms can contribute to development of acquired resistance to MET inhibitors (2011) Cancer Res., 71, pp. 1081-1091; Rosell, R., Carcereny, E., Gervais, R., Vergnenegre, A., Massuti, B., Felip, E., Palmero, R., Sanchez, J.M., Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial (2012) Lancet Oncol., 13, pp. 239-246; Salem, A.F., Whitaker-Menezes, D., Lin, Z., Martinez-Outschoorn, U.E., Tanowitz, H.B., Al-Zoubi, M.S., Howell, A., Lisanti, M.P., Two-compartment tumor metabolism: autophagy in the tumor microenvironment and oxidative mitochondrial metabolism (OXPHOS) in cancer cells (2012) Cell Cycle, 11, pp. 2545-2556; Sequist, L.V., Waltman, B.A., Dias-Santagata, D., Digumarthy, S., Turke, A.B., Fidias, P., Bergethon, K., Cosper, A.K., Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors (2011) Sci. Transl. Med., 3, p. 75ra26; Shiao, S.L., Ganesan, A.P., Rugo, H.S., Coussens, L.M., Immune microenvironments in solid tumors: new targets for therapy (2011) Genes Dev., 25, pp. 2559-2572; Smolen, G.A., Sordella, R., Muir, B., Mohapatra, G., Barmettler, A., Archibald, H., Kim, W.J., Sgroi, D.C., Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752 (2006) Proc. Natl. Acad. Sci. USA, 103, pp. 2316-2321; Sommer, C., Str{\"a}hle, C., K{\"o}the, U., (2011), pp. 230-233. , Hamprecht, F.A. ilastik: interactive learning and segmentation toolkit. Proceedings of the Eighth IEEE International Symposium on Biomedical Imaging (ISBI). IEEE; Sousa, C.M., Biancur, D.E., Wang, X., Halbrook, C.J., Sherman, M.H., Zhang, L., Kremer, D., Ying, H., Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion (2016) Nature, 536, pp. 479-483; Straussman, R., Morikawa, T., Shee, K., Barzily-Rokni, M., Qian, Z.R., Du, J., Davis, A., Frederick, D.T., Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion (2012) Nature, 487, pp. 500-504; V{\'e}gran, F., Boidot, R., Michiels, C., Sonveaux, P., Feron, O., Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-κB/IL-8 pathway that drives tumor angiogenesis (2011) Cancer Res., 71, pp. 2550-2560; Wilson, T.R., Fridlyand, J., Yan, Y., Penuel, E., Burton, L., Chan, E., Peng, J., Sosman, J., Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors (2012) Nature, 487, pp. 505-509; Yin, J., Lee, J.H., Zhang, J., Gao, Z., Polotsky, V.Y., Ye, J., Regulation of hepatocyte growth factor expression by NF-κB and PPARγ in adipose tissue (2014) Am. J. Physiol. Endocrinol. Metab., 306, pp. E929-E936; Yu, H.A., Arcila, M.E., Rekhtman, N., Sima, C.S., Zakowski, M.F., Pao, W., Kris, M.G., Riely, G.J., Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers (2013) Clin. Cancer Res., 19, pp. 2240-2247; Zeng, Q., Chen, S., You, Z., Yang, F., Carey, T.E., Saims, D., Wang, C.Y., Hepatocyte growth factor inhibits anoikis in head and neck squamous cell carcinoma cells by activation of ERK and Akt signaling independent of NFkappa B (2002) J. Biol. Chem., 277, pp. 25203-25208; Zhang, J., Liu, J., Tumor stroma as targets for cancer therapy (2013) Pharmacol. Ther., 137, pp. 200-215; Zhou, C., Wu, Y.L., Chen, G., Feng, J., Liu, X.Q., Wang, C., Zhang, S., Ren, S., Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study (2011) Lancet Oncol., 12, pp. 735-742; Zhou, M., Zhao, Y., Ding, Y., Liu, H., Liu, Z., Fodstad, O., Riker, A.I., Owen, L.B., Warburg effect in chemosensitivity: targeting lactate dehydrogenase-A re-sensitizes taxol-resistant cancer cells to taxol (2010) Mol. Cancer, 9, p. 33",
year = "2018",
doi = "10.1016/j.cmet.2018.08.006",
language = "English",
volume = "28",
pages = "848",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "6",

}

TY - JOUR

T1 - Increased Lactate Secretion by Cancer Cells Sustains Non-cell-autonomous Adaptive Resistance to MET and EGFR Targeted Therapies

AU - Apicella, M.

AU - Giannoni, E.

AU - Fiore, S.

AU - Ferrari, K.J.

AU - Fernández-Pérez, D.

AU - Isella, C.

AU - Granchi, C.

AU - Minutolo, F.

AU - Sottile, A.

AU - Comoglio, P.M.

AU - Medico, E.

AU - Pietrantonio, F.

AU - Volante, M.

AU - Pasini, D.

AU - Chiarugi, P.

AU - Giordano, S.

AU - Corso, S.

N1 - Cited By :1 Export Date: 5 February 2019 Correspondence Address: Giordano, S.; Candiolo Cancer Institute - FPO, IRCCS, Strada Provinciale 142, Italy; email: silvia.giordano@unito.it Funding details: Associazione Italiana per la Ricerca sul Cancro Funding details: Janssen Biotech Funding details: Fondazione Umberto Veronesi Funding details: Ministero della Salute Funding details: Fondazione Italiana per la Ricerca sul Cancro, FIRC Funding details: Associazione Italiana per la Ricerca sul Cancro, 20210 Funding text 1: We thank all our colleagues for helpful scientific discussion; Barbara Martinoglio and Roberta Porporato for providing technical support with real-time PCR and in situ hybridization; Paola Bernabei for technical support with FACS and sorting experiments; Stefania Giove for support with histological preparations; Francesco Fesi for hematochemical analysis; Alberto Puliafito for RNAscope quantification; employees of the animal facility; Dr. Carlos Sebastian for help with metabolic experiments; Dr. Annalisa Petrelli for support in RNAi experiments; Dr. Natale for critical reading of the manuscript. JNJ-605 was kindly provided by Janssen. This work was funded by the University of Torino , Fondo Ricerca Locale 2013 to S.C.; PROGETTO ATENEO/Compagnia San Paolo 2016, University of Torino to S.C.; the Italian Association for Cancer Research (AIRC), IG grant 20210 to S.G.; Fondazione Piemontese per la Ricerca sul Cancro (ONLUS) 5 X 1000 Fondi Ministero della Salute 2013 to A.S. and 2014 to S.G.; M.A. is a recipient of a Fondazione Veronesi Research Fellowship. References: Allen, E., Miéville, P., Warren, C.M., Saghafinia, S., Li, L., Peng, M.W., Hanahan, D., Metabolic symbiosis enables adaptive resistance to anti-angiogenic therapy that is dependent on mTOR signaling (2016) Cell Rep., 15, pp. 1144-1160; Arbiser, J.L., Raab, G., Rohan, R.M., Paul, S., Hirschi, K., Flynn, E., Price, E.R., Klagsbrun, M., Isolation of mouse stromal cells associated with a human tumor using differential diphtheria toxin sensitivity (1999) Am. J. Pathol., 155, pp. 723-729; Bacci, M., Giannoni, E., Fearns, A., Ribas, R., Gao, Q., Taddei, M.L., Pintus, G., Martin, L.A., miR-155 drives metabolic reprogramming of ER+ breast cancer cells following long-term estrogen deprivation and predicts clinical response to aromatase inhibitors (2016) Cancer Res., 76, pp. 1615-1626; Bhowmick, N.A., Neilson, E.G., Moses, H.L., Stromal fibroblasts in cancer initiation and progression (2004) Nature, 432, pp. 332-337; Bonuccelli, G., Tsirigos, A., Whitaker-Menezes, D., Pavlides, S., Pestell, R.G., Chiavarina, B., Frank, P.G., Martinez-Outschoorn, U.E., Ketones and lactate “fuel” tumor growth and metastasis: evidence that epithelial cancer cells use oxidative mitochondrial metabolism (2010) Cell Cycle, 9, pp. 3506-3514; Bottaro, D.P., Rubin, J.S., Faletto, D.L., Chan, A.M., Kmiecik, T.E., Vande Woude, G.F., Aaronson, S.A., Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product (1991) Science, 251, pp. 802-804; Calvaresi, E.C., Granchi, C., Tuccinardi, T., Di Bussolo, V., Huigens, R.W., Lee, H.Y., Palchaudhuri, R., Minutolo, F., Dual targeting of the Warburg effect with a glucose-conjugated lactate dehydrogenase inhibitor (2013) ChemBioChem, 14, pp. 2263-2267; Camidge, D.R., Pao, W., Sequist, L.V., Acquired resistance to TKIs in solid tumours: learning from lung cancer (2014) Nat. Rev. Clin. Oncol., 11, pp. 473-481; Carbone, C., Moccia, T., Zhu, C., Paradiso, G., Budillon, A., Chiao, P.J., Abbruzzese, J.L., Melisi, D., Anti-VEGF treatment-resistant pancreatic cancers secrete proinflammatory factors that contribute to malignant progression by inducing an EMT cell phenotype (2011) Clin. Cancer Res., 17, pp. 5822-5832; Carrolo, M., Giordano, S., Cabrita-Santos, L., Corso, S., Vigário, A.M., Silva, S., Leirião, P., Comoglio, P.M., Hepatocyte growth factor and its receptor are required for malaria infection (2003) Nat. Med., 9, pp. 1363-1369; Cecchi, F., Lih, C.J., Lee, Y.H., Walsh, W., Rabe, D.C., Williams, P.M., Bottaro, D.P., Expression array analysis of the hepatocyte growth factor invasive program (2015) Clin. Exp. Metastasis, 32, pp. 659-676; Cepero, V., Sierra, J.R., Corso, S., Ghiso, E., Casorzo, L., Perera, T., Comoglio, P.M., Giordano, S., MET and KRAS gene amplification mediates acquired resistance to MET tyrosine kinase inhibitors (2010) Cancer Res., 70, pp. 7580-7590; Chong, C.R., Jänne, P.A., The quest to overcome resistance to EGFR-targeted therapies in cancer (2013) Nat. Med., 19, pp. 1389-1400; Comoglio, P.M., Trusolino, L., Boccaccio, C., Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy (2018) Nat. Rev. Cancer, 18, pp. 341-358; Corso, S., Ghiso, E., Cepero, V., Sierra, J.R., Migliore, C., Bertotti, A., Trusolino, L., Giordano, S., Activation of HER family members in gastric carcinoma cells mediates resistance to MET inhibition (2010) Mol. Cancer, 9, p. 121; Cross, D.A., Ashton, S.E., Ghiorghiu, S., Eberlein, C., Nebhan, C.A., Spitzler, P.J., Orme, J.P., Mellor, M.J., AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer (2014) Cancer Discov., 4, pp. 1046-1061; Cui, J.J., Targeting receptor tyrosine kinase MET in cancer: small molecule inhibitors and clinical progress (2014) J. Med. Chem., 57, pp. 4427-4453; Curtarello, M., Zulato, E., Nardo, G., Valtorta, S., Guzzo, G., Rossi, E., Esposito, G., Rasola, A., VEGF-targeted therapy stably modulates the glycolytic phenotype of tumor cells (2015) Cancer Res., 75, pp. 120-133; Dillon, R., Nilsson, C.L., Shi, S.D., Lee, N.V., Krastins, B., Greig, M.J., Discovery of a novel B-Raf fusion protein related to c-Met drug resistance (2011) J. Proteome Res., 10, pp. 5084-5094; Engelman, J.A., Settleman, J., Acquired resistance to tyrosine kinase inhibitors during cancer therapy (2008) Curr. Opin. Genet. Dev., 18, pp. 73-79; Fiaschi, T., Marini, A., Giannoni, E., Taddei, M.L., Gandellini, P., De Donatis, A., Lanciotti, M., Chiarugi, P., Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay (2012) Cancer Res., 72, pp. 5130-5140; Gherardi, E., Birchmeier, W., Birchmeier, C., Vande Woude, G., Targeting MET in cancer: rationale and progress (2012) Nat. Rev. Cancer, 12, pp. 89-103; Giordano, S., Ponzetto, C., Di Renzo, M.F., Cooper, C.S., Comoglio, P.M., Tyrosine kinase receptor indistinguishable from the c-met protein (1989) Nature, 339, pp. 155-156; Harbinski, F., Craig, V.J., Sanghavi, S., Jeffery, D., Liu, L., Sheppard, K.A., Wagner, S., Chatenay-Rivauday, C., Rescue screens with secreted proteins reveal compensatory potential of receptor tyrosine kinases in driving cancer growth (2012) Cancer Discov., 2, pp. 948-959; Harrison, P.M., Farzaneh, F., Regulation of HGF/SF gene expression in MRC-5 cells by N-acetylcysteine (2000) Biochem. Biophys. Res. Commun., 279, pp. 108-115; Hata, A.N., Niederst, M.J., Archibald, H.L., Gomez-Caraballo, M., Siddiqui, F.M., Mulvey, H.E., Maruvka, Y.E., Krishnamurthy Radhakrishna, V., Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition (2016) Nat. Med., 22, pp. 262-269; Hu, Y., Yan, C., Mu, L., Huang, K., Li, X., Tao, D., Wu, Y., Qin, J., Fibroblast-derived exosomes contribute to chemoresistance through priming cancer stem cells in colorectal cancer (2015) PLoS One, 10, p. e0125625; Jiménez-Valerio, G., Martínez-Lozano, M., Bassani, N., Vidal, A., Ochoa-de-Olza, M., Suárez, C., García-Del-Muro, X., Graupera, M., Resistance to antiangiogenic therapies by metabolic symbiosis in renal cell carcinoma PDX models and patients (2016) Cell Rep., 15, pp. 1134-1143; Kanno, T., Sudo, K., Maekawa, M., Nishimura, Y., Ukita, M., Fukutake, K., Lactate dehydrogenase M-subunit deficiency: a new type of hereditary exertional myopathy (1988) Clin. Chim. Acta, 173, pp. 89-98; Lai, I.L., Chou, C.C., Lai, P.T., Fang, C.S., Shirley, L.A., Yan, R., Mo, X., Bekaii-Saab, T., Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells (2014) Carcinogenesis, 35, pp. 2203-2213; Lennerz, J.K., Kwak, E.L., Ackerman, A., Michael, M., Fox, S.B., Bergethon, K., Lauwers, G.Y., Haber, D.A., MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib (2011) J. Clin. Oncol., 29, pp. 4803-4810; Lovly, C.M., Shaw, A.T., Molecular pathways: resistance to kinase inhibitors and implications for therapeutic strategies (2014) Clin. Cancer Res., 20, pp. 2249-2256; Maemondo, M., Inoue, A., Kobayashi, K., Sugawara, S., Oizumi, S., Isobe, H., Gemma, A., Kinoshita, I., Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR (2010) N. Engl. J. Med., 362, pp. 2380-2388; Martinez-Outschoorn, U.E., Lisanti, M.P., Sotgia, F., Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth (2014) Semin. Cancer Biol., 25, pp. 47-60; Martinez-Outschoorn, U.E., Peiris-Pagés, M., Pestell, R.G., Sotgia, F., Lisanti, M.P., Cancer metabolism: a therapeutic perspective (2017) Nat. Rev. Clin. Oncol., 14, p. 113; Meads, M.B., Gatenby, R.A., Dalton, W.S., Environment-mediated drug resistance: a major contributor to minimal residual disease (2009) Nat. Rev. Cancer, 9, pp. 665-674; Mok, T.S., Wu, Y.L., Ahn, M.J., Garassino, M.C., Kim, H.R., Ramalingam, S.S., Shepherd, F.A., Theelen, W.S., Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer (2017) N. Engl. J. Med., 376, pp. 629-640; Mok, T.S., Wu, Y.L., Thongprasert, S., Yang, C.H., Chu, D.T., Saijo, N., Sunpaweravong, P., Ichinose, Y., Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma (2009) N. Engl. J. Med., 361, pp. 947-957; Moore, M.J., Goldstein, D., Hamm, J., Figer, A., Hecht, J.R., Gallinger, S., Au, H.J., Wolff, R.A., Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group (2007) J. Clin. Oncol., 25, pp. 1960-1966; Ohashi, K., Maruvka, Y.E., Michor, F., Pao, W., Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease (2013) J. Clin. Oncol., 31, pp. 1070-1080; Pasini, D., Malatesta, M., Jung, H.R., Walfridsson, J., Willer, A., Olsson, L., Skotte, J., Jensen, O.N., Characterization of an antagonistic switch between histone H3 lysine 27 methylation and acetylation in the transcriptional regulation of Polycomb group target genes (2010) Nucleic Acids Res., 38, pp. 4958-4969; Pennacchietti, S., Cazzanti, M., Bertotti, A., Rideout, W.M., Han, M., Gyuris, J., Perera, T., Michieli, P., Microenvironment-derived HGF overcomes genetically determined sensitivity to anti-MET drugs (2014) Cancer Res., 74, pp. 6598-6609; Pennacchietti, S., Michieli, P., Galluzzo, M., Mazzone, M., Giordano, S., Comoglio, P.M., Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene (2003) Cancer Cell, 3, pp. 347-361; Peters, S., Adjei, A.A., MET: a promising anticancer therapeutic target (2012) Nat. Rev. Clin. Oncol., 9, pp. 314-326; Pietrantonio, F., Vernieri, C., Siravegna, G., Mennitto, A., Berenato, R., Perrone, F., Gloghini, A., Morano, F., Heterogeneity of acquired resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer (2017) Clin. Cancer Res., 23, pp. 2414-2422; Pisarsky, L., Bill, R., Fagiani, E., Dimeloe, S., Goosen, R.W., Hagmann, J., Hess, C., Christofori, G., Targeting metabolic symbiosis to overcome resistance to anti-angiogenic therapy (2016) Cell Rep., 15, pp. 1161-1174; Puri, N., Salgia, R., Synergism of EGFR and c-Met pathways, cross-talk and inhibition, in non-small cell lung cancer (2008) J. Carcinog., 7, p. 9; Qi, J., McTigue, M.A., Rogers, A., Lifshits, E., Christensen, J.G., Jänne, P.A., Engelman, J.A., Multiple mutations and bypass mechanisms can contribute to development of acquired resistance to MET inhibitors (2011) Cancer Res., 71, pp. 1081-1091; Rosell, R., Carcereny, E., Gervais, R., Vergnenegre, A., Massuti, B., Felip, E., Palmero, R., Sanchez, J.M., Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial (2012) Lancet Oncol., 13, pp. 239-246; Salem, A.F., Whitaker-Menezes, D., Lin, Z., Martinez-Outschoorn, U.E., Tanowitz, H.B., Al-Zoubi, M.S., Howell, A., Lisanti, M.P., Two-compartment tumor metabolism: autophagy in the tumor microenvironment and oxidative mitochondrial metabolism (OXPHOS) in cancer cells (2012) Cell Cycle, 11, pp. 2545-2556; Sequist, L.V., Waltman, B.A., Dias-Santagata, D., Digumarthy, S., Turke, A.B., Fidias, P., Bergethon, K., Cosper, A.K., Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors (2011) Sci. Transl. Med., 3, p. 75ra26; Shiao, S.L., Ganesan, A.P., Rugo, H.S., Coussens, L.M., Immune microenvironments in solid tumors: new targets for therapy (2011) Genes Dev., 25, pp. 2559-2572; Smolen, G.A., Sordella, R., Muir, B., Mohapatra, G., Barmettler, A., Archibald, H., Kim, W.J., Sgroi, D.C., Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752 (2006) Proc. Natl. Acad. Sci. USA, 103, pp. 2316-2321; Sommer, C., Strähle, C., Köthe, U., (2011), pp. 230-233. , Hamprecht, F.A. ilastik: interactive learning and segmentation toolkit. Proceedings of the Eighth IEEE International Symposium on Biomedical Imaging (ISBI). IEEE; Sousa, C.M., Biancur, D.E., Wang, X., Halbrook, C.J., Sherman, M.H., Zhang, L., Kremer, D., Ying, H., Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion (2016) Nature, 536, pp. 479-483; Straussman, R., Morikawa, T., Shee, K., Barzily-Rokni, M., Qian, Z.R., Du, J., Davis, A., Frederick, D.T., Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion (2012) Nature, 487, pp. 500-504; Végran, F., Boidot, R., Michiels, C., Sonveaux, P., Feron, O., Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-κB/IL-8 pathway that drives tumor angiogenesis (2011) Cancer Res., 71, pp. 2550-2560; Wilson, T.R., Fridlyand, J., Yan, Y., Penuel, E., Burton, L., Chan, E., Peng, J., Sosman, J., Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors (2012) Nature, 487, pp. 505-509; Yin, J., Lee, J.H., Zhang, J., Gao, Z., Polotsky, V.Y., Ye, J., Regulation of hepatocyte growth factor expression by NF-κB and PPARγ in adipose tissue (2014) Am. J. Physiol. Endocrinol. Metab., 306, pp. E929-E936; Yu, H.A., Arcila, M.E., Rekhtman, N., Sima, C.S., Zakowski, M.F., Pao, W., Kris, M.G., Riely, G.J., Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers (2013) Clin. Cancer Res., 19, pp. 2240-2247; Zeng, Q., Chen, S., You, Z., Yang, F., Carey, T.E., Saims, D., Wang, C.Y., Hepatocyte growth factor inhibits anoikis in head and neck squamous cell carcinoma cells by activation of ERK and Akt signaling independent of NFkappa B (2002) J. Biol. Chem., 277, pp. 25203-25208; Zhang, J., Liu, J., Tumor stroma as targets for cancer therapy (2013) Pharmacol. Ther., 137, pp. 200-215; Zhou, C., Wu, Y.L., Chen, G., Feng, J., Liu, X.Q., Wang, C., Zhang, S., Ren, S., Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study (2011) Lancet Oncol., 12, pp. 735-742; Zhou, M., Zhao, Y., Ding, Y., Liu, H., Liu, Z., Fodstad, O., Riker, A.I., Owen, L.B., Warburg effect in chemosensitivity: targeting lactate dehydrogenase-A re-sensitizes taxol-resistant cancer cells to taxol (2010) Mol. Cancer, 9, p. 33

PY - 2018

Y1 - 2018

N2 - The tumor microenvironment shapes cancer progression. Apicella et al. now show that cancer-associated fibroblasts play an active metabolic role in adaptive cancer drug resistance to tyrosine kinase inhibitors (TKIs). Targeting the non-cell-autonomous lactate/HGF/MET-signaling axis abrogated acquired TKI resistance in cancer models. © 2018 Elsevier Inc. The microenvironment influences cancer drug response and sustains resistance to therapies targeting receptor-tyrosine kinases. However, if and how the tumor microenvironment can be altered during treatment, contributing to resistance onset, is not known. We show that, under prolonged treatment with tyrosine kinase inhibitors (TKIs), EGFR- or MET-addicted cancer cells displayed a metabolic shift toward increased glycolysis and lactate production. We identified secreted lactate as the key molecule instructing cancer-associated fibroblasts to produce hepatocyte growth factor (HGF) in a nuclear factor κB-dependent manner. Increased HGF, activating MET-dependent signaling in cancer cells, sustained resistance to TKIs. Functional or pharmacological targeting of molecules involved in the lactate axis abrogated in vivo resistance, demonstrating the crucial role of this metabolite in the adaptive process. This adaptive resistance mechanism was observed in lung cancer patients progressed on EGFR TKIs, demonstrating the clinical relevance of our findings and opening novel scenarios in the challenge to drug resistance. © 2018 Elsevier Inc.

AB - The tumor microenvironment shapes cancer progression. Apicella et al. now show that cancer-associated fibroblasts play an active metabolic role in adaptive cancer drug resistance to tyrosine kinase inhibitors (TKIs). Targeting the non-cell-autonomous lactate/HGF/MET-signaling axis abrogated acquired TKI resistance in cancer models. © 2018 Elsevier Inc. The microenvironment influences cancer drug response and sustains resistance to therapies targeting receptor-tyrosine kinases. However, if and how the tumor microenvironment can be altered during treatment, contributing to resistance onset, is not known. We show that, under prolonged treatment with tyrosine kinase inhibitors (TKIs), EGFR- or MET-addicted cancer cells displayed a metabolic shift toward increased glycolysis and lactate production. We identified secreted lactate as the key molecule instructing cancer-associated fibroblasts to produce hepatocyte growth factor (HGF) in a nuclear factor κB-dependent manner. Increased HGF, activating MET-dependent signaling in cancer cells, sustained resistance to TKIs. Functional or pharmacological targeting of molecules involved in the lactate axis abrogated in vivo resistance, demonstrating the crucial role of this metabolite in the adaptive process. This adaptive resistance mechanism was observed in lung cancer patients progressed on EGFR TKIs, demonstrating the clinical relevance of our findings and opening novel scenarios in the challenge to drug resistance. © 2018 Elsevier Inc.

KW - CAFs

KW - EGFR

KW - HGF/MET

KW - lactate

KW - LDH

KW - MCT1/4

KW - resistance

KW - targeted therapy

KW - tumor metabolism

KW - tumor microenvironment

U2 - 10.1016/j.cmet.2018.08.006

DO - 10.1016/j.cmet.2018.08.006

M3 - Article

VL - 28

SP - 848

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 6

ER -