Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press27010.17650/2313-805X-2020-7-2-8-19REVIEW ARTICLESОБЗОРНЫЕ СТАТЬИThe interplay of autophagy and epithelial-to-mesenchymal transition in cancer progressionВзаимодействие аутофагии и эпителиально-мезенхимального перехода в развитии опухолевой прогрессииhttps://orcid.org/0000-0001-6295-3497RyabayaO. O.РябаяО. О.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478

Оксана Олеговна Рябая 

115478 Москва, Каширское шоссе, 24

oxa2601@yandex.ruhttps://orcid.org/0000-0002-5281-2559ProkofievaA. A.ПрокофьеваА. А.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России15052020728190609202006092020Copyright ©; 2020, Ryabaya O.O., Prokofieva A.A.Copyright ©; 2020, Рябая О.О., Прокофьева А.А.2020Ryabaya O.O., Prokofieva A.A.Рябая О.О., Прокофьева А.А.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/270

Autophagy and epithelial-to-mesenchymal transition (EMT) are the main biological processes involved in tumor progression, and are closely linked. On the one hand, activation of autophagy provides energy and essential nutrients for EMT during the metastases spreading, which is required for tumor cells survival in adverse environmental conditions. On the other hand, autophagy, acting as a tumor suppressor, tends to inhibit metastasis by selectively suppressing the transcription factors of EMT in the early stages. Therefore, inhibition of EMT by inhibitors or inducers of autophagy may be a new strategy for antitumor therapy. Thus, the aim of this review is to highlight current knowledge about the crosstalk between autophagy and EMT processes in tumor progression and to summarize data supporting the necessity of parallel regulation of two processes through signaling pathways.

Аутофагия и эпителиально-мезенхимальный переход (ЭМП) являются основными биологическими процессами, участвующими в опухолевой прогрессии, и тесно взаимосвязаны между собой. С одной стороны, активация аутофагии обеспечивает энергию и основные питательные вещества для ЭМП во время распространения метастазов, что помогает клеткам выживать в неблагоприятных условиях окружающей среды. С другой стороны, аутофагия, выступающая в качестве функции, подавляющей опухолевый рост, склонна препятствовать метастазированию путем избирательного подавления основных транскрипционных факторов ЭМП на ранних стадиях. Следовательно, воздействие на ЭМП ингибиторами или активаторами аутофагии может быть стратегией, которая позволит предположить новые мишени для противоопухолевой терапии. Цель данного обзора – освещение современных знаний о перекрестном взаимодействии процессов аутофагии и ЭМП в развитии опухолевой прогрессии и суммирование данных, поддерживающих параллельное регулирование этих двух процессов через общие пути сигнализации.

epithelial-to-mesenchymal transitionautophagymetastasistumor progressionэпителиально-мезенхимальный переходаутофагияметастазированиеопухолевая прогрессияThis work was supported by Russian Foundation for Basic Research (grant No 19-015-00447).Работа выполнена при финансовой поддержке Российского фонда фундаментальных исследований (грант № 19-015-00447).1. Levine B., Kroemer G. Autophagy in the Pathogenesis of Disease. Cell 2008;132:27–42. DOI: 10.1016/j.cell.2007.12.018.Levine B., Kroemer G. Autophagy in the Pathogenesis of Disease. Cell 2008;132:27–42. DOI: 10.1016/j.cell.2007.12.018.2. Kalluri R., Weinberg R.A. The basics of epithelial-mesenchymal transition. J Clin Invest 2009;119(6):1420–8. DOI: 10.1172/JCI39104.Kalluri R., Weinberg R.A. The basics of epithelial-mesenchymal transition. J Clin Invest 2009;119(6):1420–8. DOI: 10.1172/JCI39104.3. Singh A., Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 2010;29:4741–51. DOI: 10.1038/onc.2010.215.Singh A., Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 2010;29:4741–51. DOI: 10.1038/onc.2010.215.4. Глушанкова Н.А., Житняк И.Ю., Рубцова С.Н. Роль эпителиально-мезенхимального перехода в опухолевой прогрессии. Биохимия 2018;83:1802–11. DOI: 10.1134/S0320972518120059. [Glushankova N.A., Zhitnyak I.Yu., Rubtsova S.N. The role of the epithelialmesenchymal transition in tumor progression. Biokhimiya = Biochemistry 2018;83:1802–11. (In Russ.)].Глушанкова Н.А., Житняк И.Ю., Рубцова С.Н. Роль эпителиально-мезенхимального перехода в опухолевой прогрессии. Биохимия 2018;83:1802–11. DOI: 10.1134/S0320972518120059. [Glushankova N.A., Zhitnyak I.Yu., Rubtsova S.N. The role of the epithelialmesenchymal transition in tumor progression. Biokhimiya = Biochemistry 2018;83:1802–11. (In Russ.)].5. Byers L.A., Diao L., Wang J. et al. An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin Cancer Res 2013;19:279–90. DOI: 10.1158/1078-0432.CCR-12-1558.Byers L.A., Diao L., Wang J. et al. An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin Cancer Res 2013;19:279–90. DOI: 10.1158/1078-0432.CCR-12-1558.6. Ramachandran V., Wang H., Arumugam T. et al. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res 2009;69:5820–8. DOI: 10.1158/0008-5472.can-08-2819.Ramachandran V., Wang H., Arumugam T. et al. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res 2009;69:5820–8. DOI: 10.1158/0008-5472.can-08-2819.7. Saxena M., Stephens M.A., Pathak H. et al. Transcription factors that mediate epithelial-mesenchymal transition lead to multidrug resistance by upregulating ABC transporters. Cell Death Dis 2011;2: e179. DOI: 10.1038/cddis.2011.61.Saxena M., Stephens M.A., Pathak H. et al. Transcription factors that mediate epithelial-mesenchymal transition lead to multidrug resistance by upregulating ABC transporters. Cell Death Dis 2011;2: e179. DOI: 10.1038/cddis.2011.61.8. Yang X., Yu D.D., Yan F. et al. The role of autophagy induced by tumor microenvironment in different cells and stages of cancer. Cell Biosci 2015;5:14. DOI: 10.1186/s13578-015-0005-2.Yang X., Yu D.D., Yan F. et al. The role of autophagy induced by tumor microenvironment in different cells and stages of cancer. Cell Biosci 2015;5:14. DOI: 10.1186/s13578-015-0005-2.9. Maes H., Rubio N., Garg A.D. et al. Autophagy: Shaping the tumor microenvironment and therapeutic response. Trends Mol Med 2013;19(7):428–46. DOI: 10.1016/j.molmed.2013.04.005.Maes H., Rubio N., Garg A.D. et al. Autophagy: Shaping the tumor microenvironment and therapeutic response. Trends Mol Med 2013;19(7):428–46. DOI: 10.1016/j.molmed.2013.04.005.10. Mizushima N., Yoshimori T., Ohsumi Y. The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol 2011;27:107–32. DOI: 10.1146/annurev-cellbio-092910-154005.Mizushima N., Yoshimori T., Ohsumi Y. The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol 2011;27:107–32. DOI: 10.1146/annurev-cellbio-092910-154005.11. Ryabaya O.O., Egorova A.V., Stepanova E.V. The role of autophagy in mechanisms of tumor cell death. Biol Bull Rev 2015;5:579–88. DOI: 10.1134/s2079086415060067.Ryabaya O.O., Egorova A.V., Stepanova E.V. The role of autophagy in mechanisms of tumor cell death. Biol Bull Rev 2015;5:579–88. DOI: 10.1134/s2079086415060067.12. Liang X.H., Jackson S., Seaman M. et al. Induction of autophagy and inhibition of tumorigenesis by Beclin 1. Nature 1999;402(6762):672–6. DOI: 10.1038/45257.Liang X.H., Jackson S., Seaman M. et al. Induction of autophagy and inhibition of tumorigenesis by Beclin 1. Nature 1999;402(6762):672–6. DOI: 10.1038/45257.13. Klionsky D.J., Abdelmohsen K., Abe A. et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edn.). Autophagy 2016;12:1–222. DOI: 10.1080/15548627.2015.1100356.Klionsky D.J., Abdelmohsen K., Abe A. et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edn.). Autophagy 2016;12:1–222. DOI: 10.1080/15548627.2015.1100356.14. Chen H.T., Liu H., Mao M.J. et al. Crosstalk between autophagy and epithelial-mesenchymal transition and its application in cancer therapy. Mol Cancer 2019;18:101. DOI: 10.1186/s12943-019-1030-2.Chen H.T., Liu H., Mao M.J. et al. Crosstalk between autophagy and epithelial-mesenchymal transition and its application in cancer therapy. Mol Cancer 2019;18:101. DOI: 10.1186/s12943-019-1030-2.15. Gugnoni M., Sancisi V., Manzotti G. et al. Autophagy and epithelial-mesenchymal transition: an intricate interplay in cancer. Cell Death Dis 2016;7:e2520. DOI: 10.1038/cddis.2016.415.Gugnoni M., Sancisi V., Manzotti G. et al. Autophagy and epithelial-mesenchymal transition: an intricate interplay in cancer. Cell Death Dis 2016;7:e2520. DOI: 10.1038/cddis.2016.415.16. Menzies F.M., Fleming A., Rubinsztein D.C. Compromised autophagy and neurodegenerative diseases. Nat Rev Neurosci 2015;16(6):345–57. DOI: 10.1038/nrn3961.Menzies F.M., Fleming A., Rubinsztein D.C. Compromised autophagy and neurodegenerative diseases. Nat Rev Neurosci 2015;16(6):345–57. DOI: 10.1038/nrn3961.17. Sharifi M.N., Mowers E.E., Drake L.E. et al. Autophagy promotes focal adhesion disassembly and cell motility of metastatic tumor cells through the direct interaction of paxillin with LC3. Cell Rep 2016;15:1660–72. DOI: 10.1016/j.celrep.2016.04.065.Sharifi M.N., Mowers E.E., Drake L.E. et al. Autophagy promotes focal adhesion disassembly and cell motility of metastatic tumor cells through the direct interaction of paxillin with LC3. Cell Rep 2016;15:1660–72. DOI: 10.1016/j.celrep.2016.04.065.18. Kenific C.M., Stehbens S.J., Goldsmith J. et al. NBR1 enables autophagy-dependent focal adhesion turnover. J Cell Biol 2016;212: 577–90. DOI: 10.1083/jcb.201503075.Kenific C.M., Stehbens S.J., Goldsmith J. et al. NBR1 enables autophagy-dependent focal adhesion turnover. J Cell Biol 2016;212: 577–90. DOI: 10.1083/jcb.201503075.19. Yang L., Shang Z., Long S. et al. Roles of genetic and microenvironmental factors in cancer epithelial-to-mesenchymal transition and therapeutic implication. Exp Cell Res 2018;370:190–7. DOI: 10.1016/j.yexcr.2018.07.046.Yang L., Shang Z., Long S. et al. Roles of genetic and microenvironmental factors in cancer epithelial-to-mesenchymal transition and therapeutic implication. Exp Cell Res 2018;370:190–7. DOI: 10.1016/j.yexcr.2018.07.046.20. Singla M., Bhattacharyya S. Autophagy as a potential therapeutic target during epithelial to mesenchymal transition in renal cell carcinoma: an in vitro study. Biomed Pharmacother 2017;94:332–40. DOI: 10.1016/j.biopha.2017.07.070.Singla M., Bhattacharyya S. Autophagy as a potential therapeutic target during epithelial to mesenchymal transition in renal cell carcinoma: an in vitro study. Biomed Pharmacother 2017;94:332–40. DOI: 10.1016/j.biopha.2017.07.070.21. Catalano M., D’Alessandro G., Lepore F. et al. Autophagy induction impairs migration and invasion by reversing EMT in glioblastoma cells. Mol Oncol 2015;9:1612–25. DOI: 10.1016/j.molonc.2015.04.016.Catalano M., D’Alessandro G., Lepore F. et al. Autophagy induction impairs migration and invasion by reversing EMT in glioblastoma cells. Mol Oncol 2015;9:1612–25. DOI: 10.1016/j.molonc.2015.04.016.22. Akalay I., Janji B., Hasmim M. et al. Epithelial-to-mesenchymal transition and autophagy induction in breast carcinoma promote escape from T-cell-mediated lysis. Cancer Res 2013;73:2418–27. DOI: 10.1158/0008-5472.CAN-12-2432.Akalay I., Janji B., Hasmim M. et al. Epithelial-to-mesenchymal transition and autophagy induction in breast carcinoma promote escape from T-cell-mediated lysis. Cancer Res 2013;73:2418–27. DOI: 10.1158/0008-5472.CAN-12-2432.23. Peng Y.F., Shi Y.H., Ding Z.B. et al. Autophagy inhibition suppresses pulmonary metastasis of HCC in mice via impairing anoikis resistance and colonization of HCC cells. Autophagy 2013;9:2056–68. DOI: 10.4161/auto.26398.Peng Y.F., Shi Y.H., Ding Z.B. et al. Autophagy inhibition suppresses pulmonary metastasis of HCC in mice via impairing anoikis resistance and colonization of HCC cells. Autophagy 2013;9:2056–68. DOI: 10.4161/auto.26398.24. Massagué J. TGF-β signalling in context. Nat Rev Mol Cell Biol 2012;13:616–30. DOI: 10.1038/nrm3434.Massagué J. TGF-β signalling in context. Nat Rev Mol Cell Biol 2012;13:616–30. DOI: 10.1038/nrm3434.25. Bertrand M., Petit V., Jain A. et al. SQSTM1/p62 regulates the expression of junctional proteins through epithelialmesenchymal transition factors. Cell Cycle 2015;14:364–74. DOI: 10.4161/15384101.2014.987619.Bertrand M., Petit V., Jain A. et al. SQSTM1/p62 regulates the expression of junctional proteins through epithelialmesenchymal transition factors. Cell Cycle 2015;14:364–74. DOI: 10.4161/15384101.2014.987619.26. Su Z., Li G., Liu C. et al. Autophagy inhibition impairs the epithelialmesenchymal transition and enhances cisplatin sensitivity in nasopharyngeal carcinoma. Oncol Lett 2017;13:4147–54. DOI: 10.3892/ol.2017.5963.Su Z., Li G., Liu C. et al. Autophagy inhibition impairs the epithelialmesenchymal transition and enhances cisplatin sensitivity in nasopharyngeal carcinoma. Oncol Lett 2017;13:4147–54. DOI: 10.3892/ol.2017.5963.27. Wang J.Y., Wu T., Ma W. et al. Expression and clinical significance of autophagic protein LC3B and EMT markers in gastric cancer. Cancer Manag Res 2018;10:1479–86. DOI: 10.2147/CMAR.S164842.Wang J.Y., Wu T., Ma W. et al. Expression and clinical significance of autophagic protein LC3B and EMT markers in gastric cancer. Cancer Manag Res 2018;10:1479–86. DOI: 10.2147/CMAR.S164842.28. Perera R.M., Di Malta C., Ballabio A. MiT/TFE family of transcription factors, lysosomes, and cancer. Annu Rev Cancer Biol 2019;3:203–22. DOI: 10.1146/annurev-cancerbio-030518-055835.Perera R.M., Di Malta C., Ballabio A. MiT/TFE family of transcription factors, lysosomes, and cancer. Annu Rev Cancer Biol 2019;3:203–22. DOI: 10.1146/annurev-cancerbio-030518-055835.29. Switon K., Kotulska K., JanuszKaminska A. et al. Molecular neurobiology of mTOR. Neuroscience 2017;341:112–53. DOI: 10.1016/j.neuroscience.2016.11.017.Switon K., Kotulska K., JanuszKaminska A. et al. Molecular neurobiology of mTOR. Neuroscience 2017;341:112–53. DOI: 10.1016/j.neuroscience.2016.11.017.30. Guo S., Liang X., Guo M. et al. Migration inhibition of water stress proteins from Nostoc commune Vauch. via activation of autophagy in DLD-1 cells. Int J Biol Macromol 2018;119:669–76. DOI: 10.1016/j.ijbiomac.2018.07.188.Guo S., Liang X., Guo M. et al. Migration inhibition of water stress proteins from Nostoc commune Vauch. via activation of autophagy in DLD-1 cells. Int J Biol Macromol 2018;119:669–76. DOI: 10.1016/j.ijbiomac.2018.07.188.31. Fenouille N., Tichet M., Dufies M. et al. The epithelial-mesenchymal transition (EMT) regulatory factor SLUG (SNAI2) is a downstream target of SPARC and AKT in promoting melanoma cell invasion. PLoS One 2012;7:e40378. DOI: 10.1371/journal.pone.0040378.Fenouille N., Tichet M., Dufies M. et al. The epithelial-mesenchymal transition (EMT) regulatory factor SLUG (SNAI2) is a downstream target of SPARC and AKT in promoting melanoma cell invasion. PLoS One 2012;7:e40378. DOI: 10.1371/journal.pone.0040378.32. Lamouille S., Connolly E., Smyth J.W. et al. TGf-β-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion. Development 2012;125(Pt 5):1259–73. DOI: 10.1242/jcs.095299.Lamouille S., Connolly E., Smyth J.W. et al. TGf-β-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion. Development 2012;125(Pt 5):1259–73. DOI: 10.1242/jcs.095299.33. Rogers G.W., Komar A.A., Merrick W.C. eIF4A: The godfather of the DEAD box helicases. Prog Nucleic Acid Res Mol Biol 2002;72:307–31. DOI: 10.1016/s0079-6603(02)72073-4.Rogers G.W., Komar A.A., Merrick W.C. eIF4A: The godfather of the DEAD box helicases. Prog Nucleic Acid Res Mol Biol 2002;72:307–31. DOI: 10.1016/s0079-6603(02)72073-4.34. Jordà M., Olmeda D., Vinyals A. et al. Upregulation of MMP-9 in MDCK epithelial cell line in response to expression of the Snail transcription factor. J Cell Sci 2005;118(Pt 5):3371–85. DOI: 10.1242/jcs.02465.Jordà M., Olmeda D., Vinyals A. et al. Upregulation of MMP-9 in MDCK epithelial cell line in response to expression of the Snail transcription factor. J Cell Sci 2005;118(Pt 5):3371–85. DOI: 10.1242/jcs.02465.35. Li L., Pan X.Y., Shu J. et al. Ribonuclease inhibitor up-regulation inhibits the growth and induces apoptosis in murine melanoma cells through repression of angiogenin and ILK/PI3K/AKT signaling pathway. Biochimie 2014;103:89–100. DOI: 10.1016/j.biochi.2014.04.007.Li L., Pan X.Y., Shu J. et al. Ribonuclease inhibitor up-regulation inhibits the growth and induces apoptosis in murine melanoma cells through repression of angiogenin and ILK/PI3K/AKT signaling pathway. Biochimie 2014;103:89–100. DOI: 10.1016/j.biochi.2014.04.007.36. Xu W., Yang Z., Lu N. A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition. Cell Adhes Migr 2015;9:317–24. DOI: 10.1080/19336918.2015.1016686.Xu W., Yang Z., Lu N. A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition. Cell Adhes Migr 2015;9:317–24. DOI: 10.1080/19336918.2015.1016686.37. Maier H.J., Schmidt-Straßburger U., Huber M.A. et al. NF-κB promotes epithelial-mesenchymal transition, migration and invasion of pancreatic carcinoma cells. Cancer Lett 2010;295:214–28. DOI: 10.1016/j.canlet.2010.03.003.Maier H.J., Schmidt-Straßburger U., Huber M.A. et al. NF-κB promotes epithelial-mesenchymal transition, migration and invasion of pancreatic carcinoma cells. Cancer Lett 2010;295:214–28. DOI: 10.1016/j.canlet.2010.03.003.38. O’Farrell F., Rusten T.E., Stenmark H. Phosphoinositide 3-kinases as accelerators and brakes of autophagy. FEBS J 2013;280(24):6322–37. DOI: 10.1111/febs.12486.O’Farrell F., Rusten T.E., Stenmark H. Phosphoinositide 3-kinases as accelerators and brakes of autophagy. FEBS J 2013;280(24):6322–37. DOI: 10.1111/febs.12486.39. Zong H., Yin B., Zhou H. et al. Inhibition of mTOR pathway attenuates migration and invasion of gallbladder cancer via EMT inhibition. Mol Biol Rep 2014;41:4507–12. DOI: 10.1007/s11033-014-3321-4.Zong H., Yin B., Zhou H. et al. Inhibition of mTOR pathway attenuates migration and invasion of gallbladder cancer via EMT inhibition. Mol Biol Rep 2014;41:4507–12. DOI: 10.1007/s11033-014-3321-4.40. Han B., Cui H., Kang L. et al. Metformin inhibits thyroid cancer cell growth, migration, and EMT through the mTOR pathway. Tumor Biol 2015;36(8):6295–304. DOI: 10.1007/s13277-015-3315-4.Han B., Cui H., Kang L. et al. Metformin inhibits thyroid cancer cell growth, migration, and EMT through the mTOR pathway. Tumor Biol 2015;36(8):6295–304. DOI: 10.1007/s13277-015-3315-4.41. Inoki K., Kim J., Guan K.L. AMPK and mTOR in cellular energy homeostasis and drug targets. Annu Rev Pharmacol Toxicol 2012;52:381–400. DOI: 10.1146/annurev-pharmtox-010611-134537.Inoki K., Kim J., Guan K.L. AMPK and mTOR in cellular energy homeostasis and drug targets. Annu Rev Pharmacol Toxicol 2012;52:381–400. DOI: 10.1146/annurev-pharmtox-010611-134537.42. Wang P., Jiang L., Zhou N. et al. Resveratrol ameliorates autophagic flux to promote functional recovery in rats after spinal cord injury. Oncotarget 2018;9(9):8427–40. DOI: 10.18632/oncotarget.23877.Wang P., Jiang L., Zhou N. et al. Resveratrol ameliorates autophagic flux to promote functional recovery in rats after spinal cord injury. Oncotarget 2018;9(9):8427–40. DOI: 10.18632/oncotarget.23877.43. Sun A., Li C., Chen R. et al. GSK-3β controls autophagy by modulating LKB1- AMPK pathway in prostate cancer cells. Prostate 2016;76:172–83. DOI: 10.1002/pros.23106.Sun A., Li C., Chen R. et al. GSK-3β controls autophagy by modulating LKB1- AMPK pathway in prostate cancer cells. Prostate 2016;76:172–83. DOI: 10.1002/pros.23106.44. Chang H.W., Lee Y.S., Nam H.Y. et al. Knockdown of β-catenin controls both apoptotic and autophagic cell death through LKB1/AMPK signaling in head and neck squamous cell carcinoma cell lines. Cell Signal 2013;25:839–47. DOI: 10.1016/j.cellsig.2012.12.020.Chang H.W., Lee Y.S., Nam H.Y. et al. Knockdown of β-catenin controls both apoptotic and autophagic cell death through LKB1/AMPK signaling in head and neck squamous cell carcinoma cell lines. Cell Signal 2013;25:839–47. DOI: 10.1016/j.cellsig.2012.12.020.45. Jiao D., Wang J., Lu W. et al. Curcumin inhibited HGF-induced EMT and angiogenesis through regulating c-Met dependent PI3K/Akt/mTOR signaling pathways in lung cancer. Mol Ther Oncolytics 2016;3:16018. DOI: 10.1038/mto.2016.18.Jiao D., Wang J., Lu W. et al. Curcumin inhibited HGF-induced EMT and angiogenesis through regulating c-Met dependent PI3K/Akt/mTOR signaling pathways in lung cancer. Mol Ther Oncolytics 2016;3:16018. DOI: 10.1038/mto.2016.18.46. Chang L., Graham P.H., Hao J. et al. Acquisition of epithelial-mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/ Akt/mTOR pathway in prostate cancer radioresistance. Cell Death Dis 2013;4(10):e875. DOI: 10.1038/cddis.2013.407.Chang L., Graham P.H., Hao J. et al. Acquisition of epithelial-mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/ Akt/mTOR pathway in prostate cancer radioresistance. Cell Death Dis 2013;4(10):e875. DOI: 10.1038/cddis.2013.407.47. Huang W., Yu L.F., Zhong J. et al. Stat3 is involved in angiotensin II-induced expression of MMP2 in gastric cancer cells. Dig Dis Sci 2009;54:2056–62. DOI: 10.1007/s10620-008-0617-z.Huang W., Yu L.F., Zhong J. et al. Stat3 is involved in angiotensin II-induced expression of MMP2 in gastric cancer cells. Dig Dis Sci 2009;54:2056–62. DOI: 10.1007/s10620-008-0617-z.48. Liu S.C., Huang C.M., Bamodu O.A. et al. Ovatodiolide suppresses nasopharyngeal cancer by targeting stem cell-like population, inducing apoptosis, inhibiting EMT and dysregulating JAK/ STAT signaling pathway. Phytomedicine 2019;56:269–78. DOI: 10.1016/j.phymed.2018.05.007.Liu S.C., Huang C.M., Bamodu O.A. et al. Ovatodiolide suppresses nasopharyngeal cancer by targeting stem cell-like population, inducing apoptosis, inhibiting EMT and dysregulating JAK/ STAT signaling pathway. Phytomedicine 2019;56:269–78. DOI: 10.1016/j.phymed.2018.05.007.49. Maycotte P., Jones K.L., Goodall M.L. et al. Autophagy supports breast cancer stem cell maintenance by regulating IL6 secretion. Mol Cancer Res 2015;13:651–8. DOI: 10.1158/1541-7786.MCR-14-0487.Maycotte P., Jones K.L., Goodall M.L. et al. Autophagy supports breast cancer stem cell maintenance by regulating IL6 secretion. Mol Cancer Res 2015;13:651–8. DOI: 10.1158/1541-7786.MCR-14-0487.50. Granato M., Rizzello C., Montani M.S.G. et al. Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting PI3K/AKT/mTOR and STAT3 signaling pathways. J Nutr Biochem 2017;41:124–36. DOI: 10.1016/j.jnutbio.2016.12.011.Granato M., Rizzello C., Montani M.S.G. et al. Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting PI3K/AKT/mTOR and STAT3 signaling pathways. J Nutr Biochem 2017;41:124–36. DOI: 10.1016/j.jnutbio.2016.12.011.51. Ferraresi A., Phadngam S., Morani F. et al. Resveratrol inhibits IL-6-induced ovarian cancer cell migration through epigenetic up-regulation of autophagy. Mol Carcinog 2017;56:1164–81. DOI: 10.1002/mc.22582.Ferraresi A., Phadngam S., Morani F. et al. Resveratrol inhibits IL-6-induced ovarian cancer cell migration through epigenetic up-regulation of autophagy. Mol Carcinog 2017;56:1164–81. DOI: 10.1002/mc.22582.52. Su Z., Yang Z., Xu Y. et al. Apoptosis, autophagy, necroptosis, and cancer metastasis. Mol Cancer 2015;14:48. DOI: 10.1186/s12943-015-0321-5.Su Z., Yang Z., Xu Y. et al. Apoptosis, autophagy, necroptosis, and cancer metastasis. Mol Cancer 2015;14:48. DOI: 10.1186/s12943-015-0321-5.53. Zhou W.H., Tang F., Xu J. et al. Low expression of Beclin 1, associated with high Bcl-xL, predicts a malignant phenotype and poor prognosis of gastric cancer. Autophagy 2012;8:389–400. DOI: 10.4161/auto.18641.Zhou W.H., Tang F., Xu J. et al. Low expression of Beclin 1, associated with high Bcl-xL, predicts a malignant phenotype and poor prognosis of gastric cancer. Autophagy 2012;8:389–400. DOI: 10.4161/auto.18641.54. Pattingre S., Tassa A., Qu X. et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 2005;122:927–39. DOI: 10.1016/j.cell.2005.07.002.Pattingre S., Tassa A., Qu X. et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 2005;122:927–39. DOI: 10.1016/j.cell.2005.07.002.55. Li S., Zhang H.Y., Du Z.X. et al. Induction of epithelial-mesenchymal transition (EMT) by Beclin 1 knockdown via posttranscriptional upregulation of ZEB1 in thyroid cancer cells. Oncotarget 2016;7(43):70364–77. DOI: 10.18632/oncotarget.12217.Li S., Zhang H.Y., Du Z.X. et al. Induction of epithelial-mesenchymal transition (EMT) by Beclin 1 knockdown via posttranscriptional upregulation of ZEB1 in thyroid cancer cells. Oncotarget 2016;7(43):70364–77. DOI: 10.18632/oncotarget.12217.56. Cicchini M., Chakrabarti R., Kongara S. et al. Autophagy regulator BECN1 suppresses mammary tumorigenesis driven by WNT1 activation and following parity. Autophagy 2014;10:2036–52. DOI: 10.4161/auto.34398.Cicchini M., Chakrabarti R., Kongara S. et al. Autophagy regulator BECN1 suppresses mammary tumorigenesis driven by WNT1 activation and following parity. Autophagy 2014;10:2036–52. DOI: 10.4161/auto.34398.57. Shen H., Yin L., Deng G. et al. Knockdown of Beclin-1 impairs epithelialmesenchymal transition of colon cancer cells. J Cell Biochem 2018;119:7022–31. DOI: 10.1002/jcb.26912.Shen H., Yin L., Deng G. et al. Knockdown of Beclin-1 impairs epithelialmesenchymal transition of colon cancer cells. J Cell Biochem 2018;119:7022–31. DOI: 10.1002/jcb.26912.58. Ha J.H., Ward J.D., Radhakrishnan R. et al. Lysophosphatidic acid stimulates epithelial to mesenchymal transition marker Slug/Snail2 in ovarian cancer cells via Gai2, Src, and HIF1a signaling nexus. Oncotarget 2016;7:37664–79. DOI: 10.18632/oncotarget.9224.Ha J.H., Ward J.D., Radhakrishnan R. et al. Lysophosphatidic acid stimulates epithelial to mesenchymal transition marker Slug/Snail2 in ovarian cancer cells via Gai2, Src, and HIF1a signaling nexus. Oncotarget 2016;7:37664–79. DOI: 10.18632/oncotarget.9224.59. Qiang L., He Y.Y. Autophagy deficiency stabilizes TWIST1 to promote epithelialmesenchymal transition. Autophagy 2014; 10:1864–5. DOI: 10.4161/auto.32171.Qiang L., He Y.Y. Autophagy deficiency stabilizes TWIST1 to promote epithelialmesenchymal transition. Autophagy 2014; 10:1864–5. DOI: 10.4161/auto.32171.60. Clevers H., Nusse R. Wnt/β-catenin signaling and disease. Cell 2012;149:1192–205. DOI: 10.1016/j.cell.2012.05.012.Clevers H., Nusse R. Wnt/β-catenin signaling and disease. Cell 2012;149:1192–205. DOI: 10.1016/j.cell.2012.05.012.61. Cheng M., Xue H., Cao W. et al. RACK1 promotes Dishevelled degradation via autophagy and antagonizes Wnt signaling. J Biol Chem 2016;291(24):12871–9. DOI: 10.1074/jbc.M115.708818.Cheng M., Xue H., Cao W. et al. RACK1 promotes Dishevelled degradation via autophagy and antagonizes Wnt signaling. J Biol Chem 2016;291(24):12871–9. DOI: 10.1074/jbc.M115.708818.62. Gugnoni M., Sancisi V., Gandolfi G. et al. Cadherin-6 promotes EMT and cancer metastasis by restraining autophagy. Oncogene 2017;36(5):667–77. DOI: 10.1038/onc.2016.237.Gugnoni M., Sancisi V., Gandolfi G. et al. Cadherin-6 promotes EMT and cancer metastasis by restraining autophagy. Oncogene 2017;36(5):667–77. DOI: 10.1038/onc.2016.237.63. Huber M.A., Kraut N., Beug H. Molecular requirements for epithelialmesenchymal transition during tumor progression. Curr Opin Cell Biol 2005;17:548–58. DOI: 10.1016/j.ceb.2005.08.001.Huber M.A., Kraut N., Beug H. Molecular requirements for epithelialmesenchymal transition during tumor progression. Curr Opin Cell Biol 2005;17:548–58. DOI: 10.1016/j.ceb.2005.08.001.64. Nopparat C., Sinjanakhom P., Govitrapong P. Melatonin reverses H2O2 – induced senescence in SH-SY5Y cells by enhancing autophagy via sirtuin 1 deacetylation of the RelA/p65 subunit of NF-κB. J Pineal Res 2017;63:e12407. DOI: 10.1111/jpi.12407.Nopparat C., Sinjanakhom P., Govitrapong P. Melatonin reverses H2O2 – induced senescence in SH-SY5Y cells by enhancing autophagy via sirtuin 1 deacetylation of the RelA/p65 subunit of NF-κB. J Pineal Res 2017;63:e12407. DOI: 10.1111/jpi.12407.65. Sun X., Li L., Ma H. et al. Bisindolylmaleimide alkaloid BMA-155Cl induces autophagy and apoptosis in human hepatocarcinoma HepG-2 cells through the NF-κB p65 pathway. Acta Pharmacol Sin 2017;38:524–38. DOI: 10.1038/aps.2016.171.Sun X., Li L., Ma H. et al. Bisindolylmaleimide alkaloid BMA-155Cl induces autophagy and apoptosis in human hepatocarcinoma HepG-2 cells through the NF-κB p65 pathway. Acta Pharmacol Sin 2017;38:524–38. DOI: 10.1038/aps.2016.171.66. Wu Y., Deng J., Rychahou P.G. et al. Stabilization of Snail by NF-κB is required for inflammation-induced cell migration and invasion. Cancer Cell 2009;15(5):416–28. DOI: 10.1016/j.ccr.2009.03.016.Wu Y., Deng J., Rychahou P.G. et al. Stabilization of Snail by NF-κB is required for inflammation-induced cell migration and invasion. Cancer Cell 2009;15(5):416–28. DOI: 10.1016/j.ccr.2009.03.016.67. Huang M., Xin W. Matrine inhibiting pancreatic cells epithelial-mesenchymal transition and invasion through ROS/NF-κB/MMPs pathway. Life Sci 2018;192:55–61. DOI: 10.1016/j.lfs.2017.11.024.Huang M., Xin W. Matrine inhibiting pancreatic cells epithelial-mesenchymal transition and invasion through ROS/NF-κB/MMPs pathway. Life Sci 2018;192:55–61. DOI: 10.1016/j.lfs.2017.11.024.68. Katsuno Y., Lamouille S., Derynck R. TGF-β signaling and epithelialmesenchymal transition in cancer progression. Curr Opin Oncol 2013;25:76–84. DOI: 10.1097/CCO.0b013e32835b6371.Katsuno Y., Lamouille S., Derynck R. TGF-β signaling and epithelialmesenchymal transition in cancer progression. Curr Opin Oncol 2013;25:76–84. DOI: 10.1097/CCO.0b013e32835b6371.69. Saitoh M., Endo K., Furuya S. et al. STAT3 integrates cooperative Ras and TGF-β signals that induce Snail expression. Oncogene 2016;35:1049–57. DOI: 10.1038/onc.2015.161.Saitoh M., Endo K., Furuya S. et al. STAT3 integrates cooperative Ras and TGF-β signals that induce Snail expression. Oncogene 2016;35:1049–57. DOI: 10.1038/onc.2015.161.70. He Z.J., Zhu F.Y., Li S.S. et al. Inhibiting ROS-NF-κB-dependent autophagy enhanced brazilin-induced apoptosis in head and neck squamous cell carcinoma. Food Chem Toxicol 2017;101:55–66. DOI: 10.1016/j.fct.2017.01.002.He Z.J., Zhu F.Y., Li S.S. et al. Inhibiting ROS-NF-κB-dependent autophagy enhanced brazilin-induced apoptosis in head and neck squamous cell carcinoma. Food Chem Toxicol 2017;101:55–66. DOI: 10.1016/j.fct.2017.01.002.71. Shen J., Zhao D.S., Li M.Z. TGF-β1 promotes human gastric carcinoma SGC7901 cells invasion by inducing autophagy. Eur Rev Med Pharmacol Sci 2017;21(5):1013–9.Shen J., Zhao D.S., Li M.Z. TGF-β1 promotes human gastric carcinoma SGC7901 cells invasion by inducing autophagy. Eur Rev Med Pharmacol Sci 2017;21(5):1013–9.72. Zhang C., Zhang X., Xu R. et al. TGF-β2 initiates autophagy via Smad and nonSmad pathway to promote glioma cells’ invasion. J Exp Clin Cancer Res 2017; 36:162. DOI: 10.1186/s13046-017-0628-8.Zhang C., Zhang X., Xu R. et al. TGF-β2 initiates autophagy via Smad and nonSmad pathway to promote glioma cells’ invasion. J Exp Clin Cancer Res 2017; 36:162. DOI: 10.1186/s13046-017-0628-8.73. Hu S., Wang L., Zhang X. et al. Autophagy induces transforming growth factor-β- dependent epithelial-mesenchymal transition in hepatocarcinoma cells through cAMP response element binding signalling. J Cell Mol Med 2018;22:5518–32. DOI: 10.1111/jcmm.13825.Hu S., Wang L., Zhang X. et al. Autophagy induces transforming growth factor-β- dependent epithelial-mesenchymal transition in hepatocarcinoma cells through cAMP response element binding signalling. J Cell Mol Med 2018;22:5518–32. DOI: 10.1111/jcmm.13825.74. Sancisi V., Gandolfi G., Ragazzi M. et al. Cadherin 6 is a new RUNX2 target in TGF-β signalling pathway. PLoS One 2013;8:e75489. DOI: 10.1371/journal.pone.0075489.Sancisi V., Gandolfi G., Ragazzi M. et al. Cadherin 6 is a new RUNX2 target in TGF-β signalling pathway. PLoS One 2013;8:e75489. DOI: 10.1371/journal.pone.0075489.75. Yang M., Liu E., Tang L. et al. Emerging roles and regulation of MiT/TFE transcriptional factors. Cell Commun Signal 2018;16:31. DOI: 10.1186/s12964-018-0242-1.Yang M., Liu E., Tang L. et al. Emerging roles and regulation of MiT/TFE transcriptional factors. Cell Commun Signal 2018;16:31. DOI: 10.1186/s12964-018-0242-1.76. Möller K., Sigurbjornsdottir S., Arnthorsson A.O. et al. MITF has a central role in regulating starvationinduced autophagy in melanoma. Sci Rep 2019;9:1055. DOI: 10.1038/s41598-018-37522-6.Möller K., Sigurbjornsdottir S., Arnthorsson A.O. et al. MITF has a central role in regulating starvationinduced autophagy in melanoma. Sci Rep 2019;9:1055. DOI: 10.1038/s41598-018-37522-6.77. Xu Q., Krause M., Samoylenko A. et al. Wnt signaling in renal cell carcinoma. Cancers (Basel) 2016;8:57. DOI: 10.3390/cancers8060057.Xu Q., Krause M., Samoylenko A. et al. Wnt signaling in renal cell carcinoma. Cancers (Basel) 2016;8:57. DOI: 10.3390/cancers8060057.78. Calcagnì A., Kors L., Verschuren E. et al. Modelling TFE renal cell carcinoma in mice reveals a critical role of WNT signaling. Elife 2016;5:e17047. DOI: 10.7554/eLife.17047.Calcagnì A., Kors L., Verschuren E. et al. Modelling TFE renal cell carcinoma in mice reveals a critical role of WNT signaling. Elife 2016;5:e17047. DOI: 10.7554/eLife.17047.79. Levy C., Khaled M., Fisher D.E. MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol Med 2006;12:406–14. DOI: 10.1016/j.molmed.2006.07.008.Levy C., Khaled M., Fisher D.E. MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol Med 2006;12:406–14. DOI: 10.1016/j.molmed.2006.07.008.80. Vachtenheim J., Ondrušová L. Microphthalmia-associated transcription factor expression levels in melanoma cells contribute to cell invasion and proliferation. Exp Dermatol 2015;24:481–4. DOI: 10.1111/exd.12724.Vachtenheim J., Ondrušová L. Microphthalmia-associated transcription factor expression levels in melanoma cells contribute to cell invasion and proliferation. Exp Dermatol 2015;24:481–4. DOI: 10.1111/exd.12724.81. Hartman M.L., Czyz M. MITF in melanoma: mechanisms behind its expression and activity. Cell Mol Life Sci 2015;72:1249–60. DOI: 10.1007/s00018-014-1791-0.Hartman M.L., Czyz M. MITF in melanoma: mechanisms behind its expression and activity. Cell Mol Life Sci 2015;72:1249–60. DOI: 10.1007/s00018-014-1791-0.82. Eccles M.R., He S., Ahn A. et al. MITF and PAX3 play distinct roles in melanoma cell migration; outline of a “Genetic Switch” theory involving MITF and PAX3 in proliferative and invasive phenotypes of melanoma. Front Oncol 2013;3:229. DOI: 10.3389/fonc.2013.00229.Eccles M.R., He S., Ahn A. et al. MITF and PAX3 play distinct roles in melanoma cell migration; outline of a “Genetic Switch” theory involving MITF and PAX3 in proliferative and invasive phenotypes of melanoma. Front Oncol 2013;3:229. DOI: 10.3389/fonc.2013.00229.83. Bianchi-Smiraglia A., Bagati A., Fink E.E. et al. Microphthalmia-associated transcription factor suppresses invasion by reducing intracellular GTP pools. Oncogene 2017;36:84–96. DOI: 10.1038/onc.2016.178.Bianchi-Smiraglia A., Bagati A., Fink E.E. et al. Microphthalmia-associated transcription factor suppresses invasion by reducing intracellular GTP pools. Oncogene 2017;36:84–96. DOI: 10.1038/onc.2016.178.84. Sullivan R.J., Fisher D.E. Understanding the biology of melanoma and therapeutic implications. Hematol Oncol Clin North Am 2014;28:437–53. DOI: 10.1016/j.hoc.2014.02.007.Sullivan R.J., Fisher D.E. Understanding the biology of melanoma and therapeutic implications. Hematol Oncol Clin North Am 2014;28:437–53. DOI: 10.1016/j.hoc.2014.02.007.85. Caramel J., Papadogeorgakis E., Hill L. et al. A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma. Cancer Cell 2013;24:466–80. DOI: 10.1016/j.ccr.2013.08.018.Caramel J., Papadogeorgakis E., Hill L. et al. A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma. Cancer Cell 2013;24:466–80. DOI: 10.1016/j.ccr.2013.08.018.86. Whipple C.A., Brinckerhoff C.E. BRAF (V600E) melanoma cells secrete factors that activate stromal fibroblasts and enhance tumourigenicity. Br J Cancer 2014;111:1625–33. DOI: 10.1038/bjc.2014.452.Whipple C.A., Brinckerhoff C.E. BRAF (V600E) melanoma cells secrete factors that activate stromal fibroblasts and enhance tumourigenicity. Br J Cancer 2014;111:1625–33. DOI: 10.1038/bjc.2014.452.87. Salama A.K., Kim K.B. Trametinib (GSK1120212) in the treatment of melanoma. Expert Opin Pharmacother 2013;14:619–27. DOI: 10.1517/14656566.2013.770475.Salama A.K., Kim K.B. Trametinib (GSK1120212) in the treatment of melanoma. Expert Opin Pharmacother 2013;14:619–27. DOI: 10.1517/14656566.2013.770475.88. Ferguson J., Arozarena I., Ehrhardt M. et al. Combination of MEK and SRC inhibition suppresses melanoma cell growth and invasion. Oncogene 2013; 32:86–96. DOI: 10.1038/onc.2012.25.Ferguson J., Arozarena I., Ehrhardt M. et al. Combination of MEK and SRC inhibition suppresses melanoma cell growth and invasion. Oncogene 2013; 32:86–96. DOI: 10.1038/onc.2012.25.89. Ma X.H., Piao S.F., Dey S. et al. Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. J Clin Invest 2014;124:1406–17. DOI: 10.1172/JCI70454.Ma X.H., Piao S.F., Dey S. et al. Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. J Clin Invest 2014;124:1406–17. DOI: 10.1172/JCI70454.90. Kinsey C.G., Camolotto S.A., Boespflug A.M. et al. Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat Med 2019;25(4):620–7. DOI: 10.1038/s41591-019-0367-9.Kinsey C.G., Camolotto S.A., Boespflug A.M. et al. Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat Med 2019;25(4):620–7. DOI: 10.1038/s41591-019-0367-9.91. Kim J., Kundu M., Viollet B., Guan K.L. AMPK and mTOR regulate autophagy through direct phosphorylation of ULK1. Nat Cell Biol 2011;13(2):132–41. DOI: 10.1038/ncb2152.Kim J., Kundu M., Viollet B., Guan K.L. AMPK and mTOR regulate autophagy through direct phosphorylation of ULK1. Nat Cell Biol 2011;13(2):132–41. DOI: 10.1038/ncb2152.92. Wei S.C., Yang J. Forcing through tumor metastasis: the interplay between tissue rigidity and epithelial-mesenchymal transition. Trends Cell Biol 2016;26(2): 111–20. DOI: 10.1016/j.tcb.2015.09.009.Wei S.C., Yang J. Forcing through tumor metastasis: the interplay between tissue rigidity and epithelial-mesenchymal transition. Trends Cell Biol 2016;26(2): 111–20. DOI: 10.1016/j.tcb.2015.09.009.93. Tojkander S., Gateva G., Lappalainen P. Actin stress fibers – assembly, dynamics and biological roles. J Cell Sci 2012;125(Pt 8):1855–64. DOI: 10.1242/jcs.098087.Tojkander S., Gateva G., Lappalainen P. Actin stress fibers – assembly, dynamics and biological roles. J Cell Sci 2012;125(Pt 8):1855–64. DOI: 10.1242/jcs.098087.94. Shankar J., Nabi I.R. Actin cytoskeleton regulation of epithelial mesenchymal transition in metastatic cancer cells. PLoS One 2015;10(3):e0119954. DOI: 10.1371/journal.pone.0119954.Shankar J., Nabi I.R. Actin cytoskeleton regulation of epithelial mesenchymal transition in metastatic cancer cells. PLoS One 2015;10(3):e0119954. DOI: 10.1371/journal.pone.0119954.95. Liu C.Y., Lin H.H., Tang M.J. et al. Vimentin contributes to epithelialmesenchymal transition ancer cell mechanics by mediating cytoskeletal organization and focal adhesion maturation. Oncotarget 2015;6(18):15966–83. DOI: 10.18632/oncotarget.3862.Liu C.Y., Lin H.H., Tang M.J. et al. Vimentin contributes to epithelialmesenchymal transition ancer cell mechanics by mediating cytoskeletal organization and focal adhesion maturation. Oncotarget 2015;6(18):15966–83. DOI: 10.18632/oncotarget.3862.96. Anesti V., Scorrano L. The relationship between mitochondrial shape and function and the cytoskeleton. Biochim Biophys Acta 2006;1757(5–6):692–9. DOI: 10.1016/j.bbabio.2006.04.013.Anesti V., Scorrano L. The relationship between mitochondrial shape and function and the cytoskeleton. Biochim Biophys Acta 2006;1757(5–6):692–9. DOI: 10.1016/j.bbabio.2006.04.013.97. Zhao J., Zhang J., Yu M. et al. Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene 2013;32(40):4814–24. DOI: 10.1038/onc.2012.494.Zhao J., Zhang J., Yu M. et al. Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene 2013;32(40):4814–24. DOI: 10.1038/onc.2012.494.98. Kast D.J., Dominguez R. The Cytoskeleton-autophagy connection. Curr Biol 2017;27:R318–26. DOI: 10.1016/j.cub.2017.02.061.Kast D.J., Dominguez R. The Cytoskeleton-autophagy connection. Curr Biol 2017;27:R318–26. DOI: 10.1016/j.cub.2017.02.061.99. Kashatus J.A., Nascimento A., Myers L.J. et al. Erk2 phosphorylation of Drp1 Promotes mitochondrial fission and MAPK-driven tumor growth. Mol Cell 2015;57:537–51. DOI: 10.1016/j.molcel.2015.01.002.Kashatus J.A., Nascimento A., Myers L.J. et al. Erk2 phosphorylation of Drp1 Promotes mitochondrial fission and MAPK-driven tumor growth. Mol Cell 2015;57:537–51. DOI: 10.1016/j.molcel.2015.01.002.100. Xie Q., Wu Q., Horbinski C.M. et al. Mitochondrial control by DRP1 in brain tumor initiating cells. Nat Neurosci 2015;18:501–10. DOI: 10.1038/nn.3960.Xie Q., Wu Q., Horbinski C.M. et al. Mitochondrial control by DRP1 in brain tumor initiating cells. Nat Neurosci 2015;18:501–10. DOI: 10.1038/nn.3960.101. Ji W.K., Hatch A.L., Merrill R.A. et al. Actin filaments target the oligomeric maturation of the dynamin GTPase Drp1 to mitochondrial fission sites. Elife 2015;4:e11553. DOI: 10.7554/eLife.11553.Ji W.K., Hatch A.L., Merrill R.A. et al. Actin filaments target the oligomeric maturation of the dynamin GTPase Drp1 to mitochondrial fission sites. Elife 2015;4:e11553. DOI: 10.7554/eLife.11553.102. Xu Y., Lu S. Transforming growth factor- β1-induced epithelial to mesenchymal transition increases mitochondrial content in the A549 non-small cell lung cancer cell line. Mol Med Rep 2015;11(1):417–21. DOI: 10.3892/mmr.2014.2678.Xu Y., Lu S. Transforming growth factor- β1-induced epithelial to mesenchymal transition increases mitochondrial content in the A549 non-small cell lung cancer cell line. Mol Med Rep 2015;11(1):417–21. DOI: 10.3892/mmr.2014.2678.103. Rambold A.S., Kostelecky B., Elia N., Lippincott-Schwartz J. Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci USA 2011;108(25):10190–5. DOI: 10.1073/pnas.1107402108.Rambold A.S., Kostelecky B., Elia N., Lippincott-Schwartz J. Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci USA 2011;108(25):10190–5. DOI: 10.1073/pnas.1107402108.104. Gomes L.C., Benedetto G. Di, Scorrano L. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 2011;13(5):589–98. DOI: 10.1038/ncb2220.Gomes L.C., Benedetto G. Di, Scorrano L. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 2011;13(5):589–98. DOI: 10.1038/ncb2220.