Mitochondrial dynamics in cancer stem cells

Cellular and Molecular Life Sciences (2021)Cite this article

Abstract

Many tumors are now understood to be heterogenous cell populations arising from a minority of epithelial-like cancer stem cells (CSCs). CSCs demonstrate distinctive metabolic signatures from the more differentiated surrounding tumor bulk that confer resistance to traditional chemotherapeutic regimens and potential for tumor relapse. Many CSC phenotypes including metabolism, epithelial-to-mesenchymal transition, cellular signaling pathway activity, and others, arise from altered mitochondrial function and turnover, which are regulated by constant cycles of mitochondrial fusion and fission. Further, recycling of mitochondria through mitophagy in CSCs is associated with maintenance of reactive oxygen species levels that dictate gene expression. The protein machinery that drives mitochondrial dynamics is surprisingly simple and may represent attractive new therapeutic avenues to target CSC metabolism and selectively eradicate tumor-generating cells to reduce the risks of metastasis and relapse for a variety of tumor types.

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References:

  1. 1.

    Murphy SL, Kochanek KD, Xu J, Arias E (2015) Mortality in the United States, 2014. NCHS Data Brief No. 229

  2. 2.

    Batlle E, Clevers H (2017) Cancer stem cells revisited. Nat Med 23:1124–1134

    CAS  Article  Google Scholar 

  3. 3.

    Beck B, Blanpain C (2013) Unravelling cancer stem cell potential. Nat Rev Cancer 13:727–738

    CAS  Article  Google Scholar 

  4. 4.

    Chen J, Li Y, Yu TS et al (2012) A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488:522–526. https://doi.org/10.1038/nature11287

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Hu J, Yuan X, Xu Q et al (2012) Cancer stem cells in glioblastoma. Stem cells cancer stem cells, vol 1 stem cells cancer stem cells. Ther Appl Dis Inj 1:113–120. https://doi.org/10.1007/978-94-007-1709-1_14

    Article  Google Scholar 

  6. 6.

    Dick JE, Bonnet D (1997) Human Acute Myeloid Leukaemia is organised as a heirarchy that originates from a primitive haematopoetic cell. Nat Med 3:730–737

    Article  Google Scholar 

  7. 7.

    Tian Y, Huang Z, Wang Z et al (2014) Identification of novel molecular markers for prognosis estimation of acute myeloid leukemia: over-expression of PDCD7, FIS1 and Ang2 may indicate poor prognosis in pretreatment patients with acute myeloid leukemia. PLoS ONE 9:5–10. https://doi.org/10.1371/journal.pone.0084150

    CAS  Article  Google Scholar 

  8. 8.

    Fillmore CM, Kuperwasser C (2008) Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res 10:1–13. https://doi.org/10.1186/bcr1982

    CAS  Article  Google Scholar 

  9. 9.

    Al-Hajj M, Wicha M, Benito-Hernandez A et al (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci 100(7):3983–3988

    CAS  Article  Google Scholar 

  10. 10.

    Masciale V, Grisendi G, Banchelli F et al (2019) Isolation and identification of cancer stem-like cells in adenocarcinoma and squamous cell carcinoma of the lung: a pilot study. Front Oncol 9:1–12. https://doi.org/10.3389/fonc.2019.01394

    Article  Google Scholar 

  11. 11.

    Herreros-Pomares A, de-Maya-GironesCalabuig-Fariñas JDS et al (2019) Lung tumorspheres reveal cancer stem cell-like properties and a score with prognostic impact in resected non-small-cell lung cancer. Cell Death Dis 10:1–14. https://doi.org/10.1038/s41419-019-1898-1

    CAS  Article  Google Scholar 

  12. 12.

    De Sousa E, Melo F, Kurtova AV, Harnoss JM et al (2017) A distinct role for Lgr5 + stem cells in primary and metastatic colon cancer. Nature 543:676–680. https://doi.org/10.1038/nature21713

    CAS  Article  Google Scholar 

  13. 13.

    O’Brien CA, Pollett A, Gallinger S, Dick JE (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445:106–110. https://doi.org/10.1038/nature05372

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Bertolini G, Roz L, Perego P et al (2009) Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment. Proc Natl Acad Sci USA 106:16281–16286. https://doi.org/10.1073/pnas.0905653106

    Article  PubMed  Google Scholar 

  15. 15.

    Singh SK, Hawkins C, Clarke ID et al (2004) Identification of human brain tumour initiating cells. Nature 432:396–401. https://doi.org/10.1038/nature03128

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Prager BC, Xie Q, Bao S, Rich JN (2019) Cancer stem cells: the architects of the tumor ecosystem. Cell Stem Cell 24:41–53

    CAS  Article  Google Scholar 

  17. 17.

    Shimokawa M, Ohta Y, Nishikori S et al (2017) Visualization and targeting of LGR5 + human colon cancer stem cells. Nature 545:187–192. https://doi.org/10.1038/nature22081

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Vyas S, Zaganjor E, Haigis MC (2016) Mitochondria and Cancer. Cell 166:555–566

    CAS  Article  Google Scholar 

  19. 19.

    Chen H, Chan DC (2017) Mitochondrial dynamics in regulating the unique phenotypes of cancer and stem cells. Cell Metab 26:39–48. https://doi.org/10.1016/j.cmet.2017.05.016

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Bereiter-Hahn J, Vöth M (1994) Dynamics of mitochondria in living cells: shape changes, dislocations, fusion, and fission of mitochondria. Microsc Res Tech 27:198–219. https://doi.org/10.1002/jemt.1070270303

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Friedman JR, Lackner LL, West M et al (2011) ER tubules mark sites of mitochondrial division. Science (80-) 334:358–362. https://doi.org/10.1126/science.1207385

    CAS  Article  Google Scholar 

  22. 22.

    Ingerman E, Perkins EM, Marino M et al (2005) Dnm1 forms spirals that are structurally tailored to fit mitochondria. J Cell Biol 170:1021–1027. https://doi.org/10.1083/jcb.200506078

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Kamerkar SC, Kraus F, Sharpe AJ et al (2018) Dynamin-related protein 1 has membrane constricting and severing abilities sufficient for mitochondrial and peroxisomal fission. Nat Commun. https://doi.org/10.1038/s41467-018-07543-w

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Fonseca TB, Sánchez-Guerrero Á, Milosevic I, Raimundo N (2019) Mitochondrial fission requires DRP1 but not dynamins. Nature 570:E34–E42. https://doi.org/10.1038/s41586-019-1296-y

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Lee JE, Westrate LM, Wu H et al (2016) Multiple dynamin family members collaborate to drive mitochondrial division. Nature 540:139–143. https://doi.org/10.1038/nature20555

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Kashatus JA, Nascimento A, Myers LJ et al (2015) Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth. Mol Cell 57:537–551. https://doi.org/10.1016/j.molcel.2015.01.002

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Taguchi N, Ishihara N, Jofuku A et al (2007) Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J Biol Chem 282:11521–11529. https://doi.org/10.1074/jbc.M607279200

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Chang CR, Blackstone C (2007) Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J Biol Chem 282:21583–21587. https://doi.org/10.1074/jbc.C700083200

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Santel A, Fuller MT (2001) Control of mitochondrial morphology by a human mitofusin. J Cell Sci 114:867–874

    CAS  PubMed  Google Scholar 

  30. 30.

    Chen H, Detmer SA, Ewald AJ et al (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160:189–200. https://doi.org/10.1083/jcb.200211046

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Olichon A, Emorine LJ, Descoins E et al (2002) The human dynamin-related protein OPA1 is anchored to the mitochondrial inner membrane facing the inter-membrane space. FEBS Lett 523:171–176. https://doi.org/10.1016/S0014-5793(02)02985-X

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Olichon A, Baricault L, Gas N et al (2003) Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem 278:7743–7746. https://doi.org/10.1074/jbc.C200677200

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Ehses S, Raschke I, Mancuso G et al (2009) Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1. J Cell Biol 187:1023–1036. https://doi.org/10.1083/jcb.200906084

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Ishihara N, Fujita Y, Oka T, Mihara K (2006) Regulation of mitochondrial morphology through proteolytic cleavage of OPA1. EMBO J 25:2966–2977. https://doi.org/10.1038/sj.emboj.7601184

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Anand R, Wai T, Baker MJ et al (2014) The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission. J Cell Biol 204:919–929. https://doi.org/10.1083/jcb.201308006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Rolland SG, Motori E, Memar N et al (2013) Impaired complex IV activity in response to loss of LRPPRC function can be compensated by mitochondrial hyperfusion. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.1303872110

    Article  PubMed  Google Scholar 

  37. 37.

    Pickles S, Vigié P, Youle RJ (2018) Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr Biol 28:R170–R185. https://doi.org/10.1016/j.cub.2018.01.004

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Cho HM, Ryu JR, Jo Y et al (2019) Drp1-Zip1 interaction regulates mitochondrial quality surveillance system. Mol Cell 73:364-376.e8. https://doi.org/10.1016/j.molcel.2018.11.009

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Lazarou M, Sliter DA, Kane LA et al (2015) The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524:309–314. https://doi.org/10.1038/nature14893

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Liu L, Feng D, Chen G et al (2012) Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat Cell Biol 14:177–185. https://doi.org/10.1038/ncb2422

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Novak I, Kirkin V, McEwan DG et al (2010) Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep 11:45–51. https://doi.org/10.1038/embor.2009.256

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Gomes LC, Di BG, Scorrano L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13:589–598. https://doi.org/10.1038/ncb2220

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    St. JohnRamalho-SantosGray JCJHL et al (2005) The expression of mitochondrial DNA transcription factors during early cardiomyocyte in vitro differentiation from human embryonic stemn cells. Clon Stem Cells 7:141–153. https://doi.org/10.1089/clo.2005.7.141

    Article  Google Scholar 

  44. 44.

    Lee WTY, John JS (2015) The control of mitochondrial DNA replication during development and tumorigenesis. Ann N Y Acad Sci 1350:95–106. https://doi.org/10.1111/nyas.12873

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Prigione A, Fauler B, Lurz R et al (2010) The senescence-related mitochondrial/oxidative stress pathway is repressed in human induced pluripotent stem cells. Stem Cells 28:721–733. https://doi.org/10.1002/stem.404

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Zhang J, Khvorostov I, Hong JS et al (2011) UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells. EMBO J 30:4860–4873. https://doi.org/10.1038/emboj.2011.401

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Nagdas S, Kashatus DF (2017) The interplay between oncogenic signaling networks and mitochondrial dynamics. Antioxidants. https://doi.org/10.3390/antiox6020033

    Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Serasinghe MN, Wieder SY, Renault TT et al (2015) Mitochondrial division is requisite to RAS-induced transformation and targeted by oncogenic MAPK pathway inhibitors. Mol Cell 57:521–536. https://doi.org/10.1016/j.molcel.2015.01.003

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Prieto J, León M, Ponsoda X et al (2016) Early ERK1/2 activation promotes DRP1-dependent mitochondrial fission necessary for cell reprogramming. Nat Commun. https://doi.org/10.1038/ncomms11124

    Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Pyakurel A, Savoia C, Hess D, Scorrano L (2015) Extracellular regulated kinase phosphorylates mitofusin 1 to control mitochondrial morphology and apoptosis. Mol Cell 58:244–254. https://doi.org/10.1016/j.molcel.2015.02.021

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Tondera D, Santel A, Schwarzer R et al (2004) Knockdown of MTP18, a novel phosphatidylinositol 3-kinase-dependent protein, affects mitochondrial morphology and induces apoptosis. J Biol Chem 279:31544–31555. https://doi.org/10.1074/jbc.M404704200

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Kim DI, Lee KH, Gabr AA et al (2016) Aβ-Induced Drp1 phosphorylation through Akt activation promotes excessive mitochondrial fission leading to neuronal apoptosis. Biochim Biophys Acta Mol Cell Res 1863:2820–2834. https://doi.org/10.1016/j.bbamcr.2016.09.003

    CAS  Article  Google Scholar 

  53. 53.

    Agarwal E, Altman BJ, Ho Seo J et al (2019) Myc regulation of a mitochondrial trafficking network mediates tumor cell invasion and metastasis. Mol Cell Biol. https://doi.org/10.1128/mcb.00109-19

    Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Prieto J, Seo AY, León M et al (2018) MYC induces a hybrid energetics program early in cell reprogramming. Stem Cell Rep 11:1479–1492. https://doi.org/10.1016/j.stemcr.2018.10.018

    CAS  Article  Google Scholar 

  55. 55.

    von Eyss B, Jaenicke LA, Kortlever RM et al (2015) A MYC-driven change in mitochondrial dynamics limits YAP/TAZ function in mammary epithelial cells and breast cancer. Cancer Cell 28:743–757. https://doi.org/10.1016/j.ccell.2015.10.013

    CAS  Article  Google Scholar 

  56. 56.

    Toyama EQ, Herzig S, Courchet J et al (2016) Metabolism: AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science (80-) 351:275–281. https://doi.org/10.1126/science.aab4138

    CAS  Article  Google Scholar 

  57. 57.

    Xie Q, Wu Q, Horbinski CM et al (2015) Mitochondrial control by DRP1 in brain tumor initiating cells. Nat Neurosci 18:501–510. https://doi.org/10.1038/nn.3960

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    DeBerardinis RJ, Chandel NS (2020) We need to talk about the Warburg effect. Nat Metab 2:127–129. https://doi.org/10.1038/s42255-020-0172-2

    Article  PubMed  Google Scholar 

  59. 59.

    Sperber H, Mathieu J, Wang Y et al (2015) The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition. Nat Cell Biol 17:1523–1535. https://doi.org/10.1038/ncb3264

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Kaelin WG, McKnight SL (2013) Influence of metabolism on epigenetics and disease. Cell 153:56–69. https://doi.org/10.1016/j.cell.2013.03.004

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Lee JV, Carrer A, Shah S et al (2014) Akt-dependent metabolic reprogramming regulates tumor cell Histone acetylation. Cell Metab 20:306–319. https://doi.org/10.1016/j.cmet.2014.06.004

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Wellen KE, Hatzivassiliou G, Sachdeva UM et al (2009) ATP-citrate lyase links cellular metabolism to histone acetylation. Science (80-) 324:1076–1080. https://doi.org/10.1126/science.1164097

    CAS  Article  Google Scholar 

  63. 63.

    Carey BW, Finley LWS, Cross JR et al (2015) Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature 518:413–416. https://doi.org/10.1038/nature13981

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Selak MA, Armour SM, MacKenzie ED et al (2005) Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell 7:77–85. https://doi.org/10.1016/j.ccr.2004.11.022

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Wang C, Shao L, Pan C et al (2019) Elevated level of mitochondrial reactive oxygen species via fatty acid β-oxidation in cancer stem cells promotes cancer metastasis by inducing epithelial-mesenchymal transition. Stem Cell Res Ther. https://doi.org/10.1186/s13287-019-1265-2

    Article  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Hamanaka RB, Glasauer A, Hoover P et al (2013) Mitochondrial reactive oxygen species promote epidermal differentiation and hair follicle. Development 6:1–10

    Google Scholar 

  67. 67.

    MacKenzie ED, Selak MA, Tennant DA et al (2007) Cell-permeating α-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells. Mol Cell Biol 27:3282–3289. https://doi.org/10.1128/mcb.01927-06

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Rodríguez-Colman MJ, Schewe M, Meerlo M et al (2017) Interplay between metabolic identities in the intestinal crypt supports stem cell function. Nature 543:424–427. https://doi.org/10.1038/nature21673

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Ma R, Ma L, Weng W et al (2020) DUSP6 SUMOylation protects cells from oxidative damage via direct regulation of Drp1 dephosphorylation. Sci Adv. https://doi.org/10.1126/sciadv.aaz0361

    Article  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Xue D, Zhou X, Qiu J (2020) Emerging role of NRF2 in ROS-mediated tumor chemoresistance. Biomed Pharmacother 131:110676. https://doi.org/10.1016/j.biopha.2020.110676

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Guha M, Srinivasan S, Ruthel G et al (2014) Mitochondrial retrograde signaling induces epithelial-mesenchymal transition and generates breast cancer stem cells. Oncogene 33:5238–5250. https://doi.org/10.1038/onc.2013.467

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Srinivasan S, Koenigstein A, Joseph J et al (2010) Role of mitochondrial reactive oxygen species in osteoclast differentiation. Ann N Y Acad Sci 1192:245–252. https://doi.org/10.1111/j.1749-6632.2009.05377.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Khacho M, Clark A, Svoboda DS et al (2016) Mitochondrial dynamics impacts stem cell identity and fate decisions by regulating a nuclear transcriptional program. Cell Stem Cell 19:232–247. https://doi.org/10.1016/j.stem.2016.04.015

    CAS  Article  PubMed  Google Scholar 

  74. 74.

    Folmes CDL, Nelson TJ, Martinez-Fernandez A et al (2011) Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metab 14:264–271. https://doi.org/10.1016/j.cmet.2011.06.011

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Civenni G, Bosotti R, Timpanaro A et al (2019) Epigenetic control of mitochondrial fission enables self-renewal of stem-like tumor cells in human prostate cancer. Cell Metab 30:303-318.e6. https://doi.org/10.1016/j.cmet.2019.05.004

    CAS  Article  PubMed  Google Scholar 

  76. 76.

    Lagadinou ED, Sach A, Callahan K et al (2013) BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell 12:329–341. https://doi.org/10.1016/j.stem.2012.12.013

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Pei S, Minhajuddin M, Adane B et al (2018) AMPK/FIS1-mediated mitophagy is required for self-renewal of human AML stem cells. Cell Stem Cell 23:86-100.e6. https://doi.org/10.1016/j.stem.2018.05.021

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Ye X, Tam WL, Shibue T et al (2015) Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature 525:256–260. https://doi.org/10.1038/nature14897

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Rodríguez-García A, Samsó P, Fontova P et al (2017) TGF-β1 targets Smad, p38 MAPK, and PI3K/Akt signaling pathways to induce PFKFB3 gene expression and glycolysis in glioblastoma cells. FEBS J 284:3437–3454. https://doi.org/10.1111/febs.14201

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Masin M, Vazquez J, Rossi S et al (2014) GLUT3 is induced during epithelial-mesenchymal transition and promotes tumor cell proliferation in non-small cell lung cancer. Cancer Metab 2:11. https://doi.org/10.1186/2049-3002-2-11

    Article  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Liu M, Quek L-E, Sultani G, Turner N (2016) Epithelial-mesenchymal transition induction is associated with augmented glucose uptake and lactate production in pancreatic ductal adenocarcinoma. Cancer Metab 4:1–13. https://doi.org/10.1186/s40170-016-0160-x

    CAS  Article  Google Scholar 

  82. 82.

    Zhang Z, Li TE, Chen M et al (2020) MFN1-dependent alteration of mitochondrial dynamics drives hepatocellular carcinoma metastasis by glucose metabolic reprogramming. Br J Cancer 122:209–220. https://doi.org/10.1038/s41416-019-0658-4

    CAS  Article  PubMed  Google Scholar 

  83. 83.

    Cunniff B, McKenzie AJ, Heintz NH, Howe AK (2016) AMPK activity regulates trafficking of Mitochondria to the leading edge during cell migration and matrix invasion. Mol Biol Cell 27:2662–2674. https://doi.org/10.1091/mbc.E16-05-0286

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Caino MC, Ghosh JC, Chae YC et al (2015) PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion. Proc Natl Acad Sci USA 112:8638–8643. https://doi.org/10.1073/pnas.1500722112

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Desai SP, Bhatia SN, Toner M, Irimia D (2013) Mitochondrial localization and the persistent migration of epithelial cancer cells. Biophys J 104:2077–2088. https://doi.org/10.1016/j.bpj.2013.03.025

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Lee HC, Yin PH, Lin JC et al (2005) Mitochondrial genome instability and mtDNA depletion in human cancers. Ann N Y Acad Sci 1042:109–122. https://doi.org/10.1196/annals.1338.011

    CAS  Article  PubMed  Google Scholar 

  87. 87.

    Wu MJ, Chen YS, Kim MR et al (2019) Epithelial-mesenchymal transition directs stem cell polarity via regulation of mitofusin. Cell Metab 29:993-1002.e6. https://doi.org/10.1016/j.cmet.2018.11.004

    CAS  Article  PubMed  Google Scholar 

  88. 88.

    Whelan KA, Chandramouleeswaran PM, Tanaka K et al (2017) Autophagy supports generation of cells with high CD44 expression via modulation of oxidative stress and Parkin-mediated mitochondrial clearance. Oncogene. https://doi.org/10.1038/onc.2017.102

    Article  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Viale A, Pettazzoni P, Lyssiotis CA et al (2014) Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514:628–632. https://doi.org/10.1038/nature13611

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Kong B, Tsuyoshi H, Orisaka M et al (2015) Mitochondrial dynamics regulating chemoresistance in gynecological cancers. Ann N Y Acad Sci 1350:1–16. https://doi.org/10.1111/nyas.12883

    CAS  Article  PubMed  Google Scholar 

  91. 91.

    Zampieri LX, Grasso D, Bouzin C et al (2020) Mitochondria participate in chemoresistance to cisplatin in human ovarian cancer cells. Mol Cancer Res molcanres.1145.2019. https://doi.org/10.1158/1541-7786.mcr-19-1145

  92. 92.

    Wang T, Fahrmann JF, Lee H et al (2018) JAK/STAT3-regulated fatty acid β-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab 27:136-150.e5. https://doi.org/10.1016/j.cmet.2017.11.001

    CAS  Article  PubMed  Google Scholar 

  93. 93.

    Lee K, GiltnaneBalko JMJM et al (2017) MYC and MCL1 cooperatively promote chemotherapy-resistant breast cancer stem cells via regulation of mitochondrial oxidative phosphorylation. Cell Metab 26:633-647.e7. https://doi.org/10.1016/j.cmet.2017.09.009

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Ducker GS, Rabinowitz JD (2017) Cell metabolism review one-carbon metabolism in health and disease. Cell Metab 25:27–42. https://doi.org/10.1016/j.cmet.2016.08.009

    CAS  Article  PubMed  Google Scholar 

  95. 95.

    Nilsson R, Jain M, Madhusudhan N et al (2014) Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer. Nat Commun. https://doi.org/10.1038/ncomms4128

    Article  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Jung J, Zhang Y, Celiku O et al (2019) Mitochondrial NIX promotes tumor survival in the hypoxic niche of glioblastoma. Cancer Res canres.0198.2019. https://doi.org/10.1158/0008-5472.can-19-0198

  97. 97.

    Comerford KM, Wallace TJ, Karhausen J et al (2002) Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 62:3387–3394

    CAS  PubMed  Google Scholar 

  98. 98.

    Yan C, Luo L, Guo CY et al (2017) Doxorubicin-induced mitophagy contributes to drug resistance in cancer stem cells from HCT8 human colorectal cancer cells. Cancer Lett 388:34–42. https://doi.org/10.1016/j.canlet.2016.11.018

    CAS  Article  PubMed  Google Scholar 

  99. 99.

    Lee SY, Jeong EK, Ju MK et al (2017) Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation. Mol Cancer 16:1–25. https://doi.org/10.1186/s12943-016-0577-4

    CAS  Article  Google Scholar 

  100. 100.

    Patten DA, Ouellet M, Allan DS et al (2019) Mitochondrial adaptation in human mesenchymal stem cells following ionizing radiation. FASEB J 33:9263–9278. https://doi.org/10.1096/fj.201801483rr

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Stewart JM, Shaw PA, Gedye C et al (2011) Phenotypic heterogeneity and instability of human ovarian tumor-initiating cells. Proc Natl Acad Sci USA 108:6468–6473. https://doi.org/10.1073/pnas.1005529108

    Article  PubMed  Google Scholar 

  102. 102.

    Takeda M, Koseki J, Takahashi H et al (2019) Disruption of endolysosomal Rab5/7 efficiently eliminates colorectal cancer stem cells. Cancer Res 79:1426–1437. https://doi.org/10.1158/0008-5472.CAN-18-2192

    CAS  Article  PubMed  Google Scholar 

  103. 103.

    Adlam VJ, Harrison JC, Porteous CM et al (2005) Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury. FASEB J 19:1088–1095. https://doi.org/10.1096/fj.05-3718com

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

We thank the members of the Kashatus lab for review of the manuscript.

Funding

This work is supported by NIH grant CA200755 (to D.F.K.).

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  1. Department of Microbiology, Immunology, and Cancer Biology, University of Virginia Health System, Charlottesville, VA, 22908, USA

    Dane T. Sessions & David F. Kashatus

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  1. Dane T. Sessions
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  2. David F. Kashatus
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Correspondence to David F. Kashatus.

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Sessions, D.T., Kashatus, D.F. Mitochondrial dynamics in cancer stem cells. Cell. Mol. Life Sci. (2021). https://doi.org/10.1007/s00018-021-03773-2

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Keywords

  • Mitochondrial dynamics
  • Mitochondrial morphology
  • Cancer stem cells
  • Metabolism
  • Therapeutic resistance
  • Signaling
  • EMT