Mitochondrial transfer from Adipose stem cells to breast cancer cells drives multi-drug resistance.
Adipose Stem cells
Breast Cancer
Mitoception
Mitochondrial transfer
Multi-drug resistance
Tunneling nanotubes
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
14 Jun 2024
14 Jun 2024
Historique:
received:
02
04
2024
accepted:
01
06
2024
medline:
15
6
2024
pubmed:
15
6
2024
entrez:
14
6
2024
Statut:
epublish
Résumé
Breast cancer (BC) is a complex disease, showing heterogeneity in the genetic background, molecular subtype, and treatment algorithm. Historically, treatment strategies have been directed towards cancer cells, but these are not the unique components of the tumor bulk, where a key role is played by the tumor microenvironment (TME), whose better understanding could be crucial to obtain better outcomes. We evaluated mitochondrial transfer (MT) by co-culturing Adipose stem cells with different Breast cancer cells (BCCs), through MitoTracker assay, Mitoception, confocal and immunofluorescence analyses. MT inhibitors were used to confirm the MT by Tunneling Nano Tubes (TNTs). MT effect on multi-drug resistance (MDR) was assessed using Doxorubicin assay and ABC transporter evaluation. In addition, ATP production was measured by Oxygen Consumption rates (OCR) and Immunoblot analysis. We found that MT occurs via Tunneling Nano Tubes (TNTs) and can be blocked by actin polymerization inhibitors. Furthermore, in hybrid co-cultures between ASCs and patient-derived organoids we found a massive MT. Breast Cancer cells (BCCs) with ASCs derived mitochondria (ADM) showed a reduced HIF-1α expression in hypoxic conditions, with an increased ATP production driving ABC transporters-mediated multi-drug resistance (MDR), linked to oxidative phosphorylation metabolism rewiring. We provide a proof-of-concept of the occurrence of Mitochondrial Transfer (MT) from Adipose Stem Cells (ASCs) to BC models. Blocking MT from ASCs to BCCs could be a new effective therapeutic strategy for BC treatment.
Sections du résumé
BACKGROUND
BACKGROUND
Breast cancer (BC) is a complex disease, showing heterogeneity in the genetic background, molecular subtype, and treatment algorithm. Historically, treatment strategies have been directed towards cancer cells, but these are not the unique components of the tumor bulk, where a key role is played by the tumor microenvironment (TME), whose better understanding could be crucial to obtain better outcomes.
METHODS
METHODS
We evaluated mitochondrial transfer (MT) by co-culturing Adipose stem cells with different Breast cancer cells (BCCs), through MitoTracker assay, Mitoception, confocal and immunofluorescence analyses. MT inhibitors were used to confirm the MT by Tunneling Nano Tubes (TNTs). MT effect on multi-drug resistance (MDR) was assessed using Doxorubicin assay and ABC transporter evaluation. In addition, ATP production was measured by Oxygen Consumption rates (OCR) and Immunoblot analysis.
RESULTS
RESULTS
We found that MT occurs via Tunneling Nano Tubes (TNTs) and can be blocked by actin polymerization inhibitors. Furthermore, in hybrid co-cultures between ASCs and patient-derived organoids we found a massive MT. Breast Cancer cells (BCCs) with ASCs derived mitochondria (ADM) showed a reduced HIF-1α expression in hypoxic conditions, with an increased ATP production driving ABC transporters-mediated multi-drug resistance (MDR), linked to oxidative phosphorylation metabolism rewiring.
CONCLUSIONS
CONCLUSIONS
We provide a proof-of-concept of the occurrence of Mitochondrial Transfer (MT) from Adipose Stem Cells (ASCs) to BC models. Blocking MT from ASCs to BCCs could be a new effective therapeutic strategy for BC treatment.
Identifiants
pubmed: 38877575
doi: 10.1186/s13046-024-03087-8
pii: 10.1186/s13046-024-03087-8
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
166Informations de copyright
© 2024. The Author(s).
Références
Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rubio IT, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30:1194–220.
pubmed: 31161190
doi: 10.1093/annonc/mdz173
Gennari A, André F, Barrios CH, Cortés J, de Azambuja E, DeMichele A, et al. ESMO Guidelines Committee Electronic address: clinicalguidelines@esmo.org ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021;32(12):1475–95.
pubmed: 34678411
doi: 10.1016/j.annonc.2021.09.019
Kinnel B, Singh SK, Oprea-Ilies G, Singh R. Targeted Therapy and Mechanisms of Drug Resistance in Breast Cancer. Cancers (Basel). 2023;15(4):1320.
pubmed: 36831661
pmcid: 9954028
doi: 10.3390/cancers15041320
Mittal S, Brown NJ, Holen I. The breast tumor microenvironment: role in cancer development, progression and response to therapy. Expert Rev Mol Diagn. 2018;18(3):227–43.
pubmed: 29424261
doi: 10.1080/14737159.2018.1439382
Ritter A, Kreis NN, Hoock SC, Solbach C, Louwen F, Yuan J. Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells, Obesity and the Tumor Microenvironment of Breast Cancer. Cancers (Basel). 2022;14(16):3908.
pubmed: 36010901
pmcid: 9405791
doi: 10.3390/cancers14163908
Malla R, Puvalachetty K, Vempati RK, Marni R, Merchant N, Nagaraju GP. Cancer Stem Cells and Circulatory Tumor Cells Promote Breast Cancer Metastasis. Clin Breast Cancer. 2022;22(6):507–14.
pubmed: 35688785
doi: 10.1016/j.clbc.2022.05.004
Ritter A, Kreis NN, Roth S, Friemel A, Safdar BK, Hoock SC, et al. Cancer-educated mammary adipose tissue-derived stromal/stem cells in obesity and breast cancer: spatial regulation and function. J Exp Clin Cancer Res. 2023;42(1):35.
pubmed: 36710348
pmcid: 9885659
doi: 10.1186/s13046-022-02592-y
Amari L, Germain M. Mitochondrial Extracellular Vesicles - Origins and Roles. Front Mol Neurosci. 2021;14:767219.
pubmed: 34751216
pmcid: 8572053
doi: 10.3389/fnmol.2021.767219
Ariazi J, Benowitz A, De Biasi V, Den Boer ML, Cherqui S, Cui H, et al. Tunneling Nanotubes and Gap Junctions-Their Role in Long-Range Intercellular Communication during Development, Health, and Disease Conditions. Front Mol Neurosci. 2017;10:333.
pubmed: 29089870
pmcid: 5651011
doi: 10.3389/fnmol.2017.00333
Brestoff JR, Wilen CB, Moley JR, Li Y, Zou W, Malvin NP, et al. Intercellular Mitochondria Transfer to Macrophages Regulates White Adipose Tissue Homeostasis and Is Impaired in Obesity. Cell Metab. 2021;33(2):270–82 e8.
pubmed: 33278339
doi: 10.1016/j.cmet.2020.11.008
Matula Z, Mikala G, Lukácsi S, Matkó J, Kovács T, Monostori É, et al. Stromal Cells Serve Drug Resistance for Multiple Myeloma via Mitochondrial Transfer: A Study on Primary Myeloma and Stromal Cells. Cancers (Basel). 2021;13(14):3461.
pubmed: 34298674
pmcid: 8307863
doi: 10.3390/cancers13143461
Bukowski K, Kciuk M, Kontek R. Mechanisms of Multidrug Resistance in Cancer Chemotherapy. Int J Mol Sci. 2020May 2;21(9):3233.
pubmed: 32370233
pmcid: 7247559
doi: 10.3390/ijms21093233
Dei S, Braconi L, Romanelli MN, Teodori E. Recent advances in the search of BCRP- and dual P-gp/BCRP-based multidrug resistance modulators. Cancer Drug Resist. 2019;2(3):710–43.
pubmed: 35582565
pmcid: 8992508
Herst PM, Dawson RH, Berridge MV. Intercellular Communication in Tumor Biology: A Role for Mitochondrial Transfer. Front Oncol. 2018;8:344.
pubmed: 30211122
pmcid: 6121133
doi: 10.3389/fonc.2018.00344
Giddings EL, Champagne DP, Wu MH, Laffin JM, Thornton TM, Valenca-Pereira F, et al. Mitochondrial ATP fuels ABC transporter-mediated drug efflux in cancer chemoresistance. Nat Commun. 2021;12(1):2804.
pubmed: 33990571
pmcid: 8121950
doi: 10.1038/s41467-021-23071-6
Sancho P, Barneda D, Heeschen C. Hallmarks of cancer stem cell metabolism. Br J Cancer. 2016;114(12):1305–12.
pubmed: 27219018
pmcid: 4984474
doi: 10.1038/bjc.2016.152
Elia I, Haigis MC. Metabolites and the tumour microenvironment: from cellular mechanisms to systemic metabolism. Nat Metab. 2021;3(1):21–32.
pubmed: 33398194
pmcid: 8097259
doi: 10.1038/s42255-020-00317-z
Cirillo F, Pellegrino M, Talia M, Perrotta ID, Rigiracciolo DC, Spinelli A, et al. Estrogen receptor variant ERα46 and insulin receptor drive in primary breast cancer cells growth effects and interleukin 11 induction prompting the motility of cancer-associated fibroblasts. Clin Transl Med. 2021;11(11).
pubmed: 34841688
pmcid: 8567034
doi: 10.1002/ctm2.516
Paino F, La Noce M, Di Nucci D, Nicoletti GF, Salzillo R, De Rosa A, et al. Human adipose stem cell differentiation is highly affected by cancer cells both in vitro and in vivo: implication for autologous fat grafting. Cell Death Dis. 2017;8(1).
pubmed: 28102844
pmcid: 5386348
doi: 10.1038/cddis.2016.308
Papaccio F, García-Mico B, Gimeno-Valiente F, Cabeza-Segura M, Gambardella V, Gutiérrez-Bravo MF, et al. Proteotranscriptomic analysis of advanced colorectal cancer patient derived organoids for drug sensitivity prediction. J Exp Clin Cancer Res. 2023;42(1):8.
pubmed: 36604765
pmcid: 9817273
doi: 10.1186/s13046-022-02591-z
Caicedo A, Fritz V, Brondello JM, Ayala M, Dennemont I, Abdellaoui N, et al. MitoCeption as a new tool to assess the effects of mesenchymal stem/stromal cell mitochondria on cancer cell metabolism and function. Sci Rep. 2015;5:9073.
pubmed: 25766410
pmcid: 4358056
doi: 10.1038/srep09073
Li Q, Lau A, Morris TJ, Guo L, Fordyce CB, Stanley EF. A syntaxin 1, Galpha(o), and N-type calcium channel complex at a presynaptic nerve terminal: analysis by quantitative immunocolocalization. J Neurosci. 2004;24(16):4070–81.
pubmed: 15102922
pmcid: 6729428
doi: 10.1523/JNEUROSCI.0346-04.2004
Yin W, Xiang D, Wang T, Zhang Y, Pham CV, Zhou S, et al. The inhibition of ABCB1/MDR1 or ABCG2/BCRP enables doxorubicin to eliminate liver cancer stem cells. Sci Rep. 2021;11(1):10791.
pubmed: 34031441
pmcid: 8144399
doi: 10.1038/s41598-021-89931-9
Wang M, Zhao J, Zhang L, Wei F, Lian Y, Wu Y, et al. Role of tumor microenvironment in tumorigenesis. J Cancer. 2017;8(5):761–73.
pubmed: 28382138
pmcid: 5381164
doi: 10.7150/jca.17648
Galland S, Stamenkovic I. Mesenchymal stromal cells in cancer: a review of their immunomodulatory functions and dual effects on tumor progression. J Pathol. 2020;250(5):555–72.
pubmed: 31608444
doi: 10.1002/path.5357
Liu S, Ginestier C, Ou SJ, Clouthier SG, Patel SH, Monville F, et al. Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks. Cancer Res. 2011;71(6):2407.
doi: 10.1158/0008-5472.CAN-11-0126
Ritter A, Friemel A, Roth S, Kreis NN, Hoock SC, Safdar BK, et al. Subcutaneous and Visceral Adipose-Derived Mesenchymal Stem Cells: Commonality and Diversity. Cells. 2019;8(10):1288.
pubmed: 31640218
pmcid: 6830091
doi: 10.3390/cells8101288
Abels ER, Breakefield XO. Introduction to Extracellular Vesicles: Biogenesis, RNA Cargo Selection, Content, Release, and Uptake. Cell Mol Neurobiol. 2016;36(3):301–12.
pubmed: 27053351
pmcid: 5546313
doi: 10.1007/s10571-016-0366-z
Sabol RA, Villela VA, Denys A, Freeman BT, Hartono AB, Wise RM, et al. Obesity-Altered Adipose Stem Cells Promote Radiation Resistance of Estrogen Receptor Positive Breast Cancer through Paracrine Signaling. Int J Mol Sci. 2020Apr 15;21(8):2722.
pubmed: 32326381
pmcid: 7216284
doi: 10.3390/ijms21082722
Chan YW, So C, Yau KL, Chiu KC, Wang X, Chan FL, et al. Adipose-derived stem cells and cancer cells fuse to generate cancer stem cell-like cells with increased tumorigenicity. J Cell Physiol. 2020;235(10):6794–807.
pubmed: 31994190
doi: 10.1002/jcp.29574
Melzer C, von der Ohe J, Hass R. Enhanced metastatic capacity of breast cancer cells after interaction and hybrid formation with mesenchymal stroma/stem cells (MSC). Cell Commun Signal. 2018;16(1):2.
pubmed: 29329589
pmcid: 5795285
doi: 10.1186/s12964-018-0215-4
Rustom A, Saffrich R, Markovic I, Walther P, Gerdes HH. Nanotubular highways for intercellular organelle transport. Science. 2004;303(5660):1007–10.
pubmed: 14963329
doi: 10.1126/science.1093133
Abounit S, Zurzolo C. Wiring through tunneling nanotubes–from electrical signals to organelle transfer. J Cell Sci. 2012;125(Pt 5):1089–98.
pubmed: 22399801
doi: 10.1242/jcs.083279
Han Y, Kim B, Cho U, Park IS, Kim SI, Dhanasekaran DN, et al. Mitochondrial fission causes cisplatin resistance under hypoxic conditions via ROS in ovarian cancer cells. Oncogene. 2019;38(45):7089–105.
pubmed: 31409904
doi: 10.1038/s41388-019-0949-5
Kong B, Wang Q, Fung E, Xue K, Tsang BK. p53 is required for cisplatin-induced processing of the mitochondrial fusion protein L-Opa1 that is mediated by the mitochondrial metallopeptidase Oma1 in gynecologic cancers. J Biol Chem. 2014;289(39):27134–45.
pubmed: 25112877
pmcid: 4175349
doi: 10.1074/jbc.M114.594812
Casinelli G, LaRosa J, Sharma M, Cherok E, Banerjee S, Branca M, et al. N-Myc overexpression increases cisplatin resistance in neuroblastoma via deregulation of mitochondrial dynamics. Cell Death Discov. 2016;2:16082.
pubmed: 28028439
pmcid: 5149579
doi: 10.1038/cddiscovery.2016.82
Rossignol R, Gilkerson R, Aggeler R, Yamagata K, Remington SJ, Capaldi RA. Energy substrate modulates mitochondrial structure and oxidative capacity in cancer cells. Cancer Res. 2004;64(3):985–93.
pubmed: 14871829
doi: 10.1158/0008-5472.CAN-03-1101
Hekmatshoar Y, Nakhle J, Galloni M, Vignais ML. The role of metabolism and tunneling nanotube-mediated intercellular mitochondria exchange in cancer drug resistance. Biochem J. 2018;475(14):2305–28.
pubmed: 30064989
doi: 10.1042/BCJ20170712
Pasquier J, Guerrouahen BS, Al Thawadi H, Ghiabi P, Maleki M, Abu-Kaoud N, et al. Preferential transfer of mitochondria from endothelial to cancer cells through tunneling nanotubes modulates chemoresistance. J Transl Med. 2013;11:94.
pubmed: 23574623
pmcid: 3668949
doi: 10.1186/1479-5876-11-94
Liu D, Gao Y, Liu J, Huang Y, Yin J, Feng Y, et al. Intercellular mitochondrial transfer as a means of tissue revitalization. Signal Transduct Target Ther. 2021;6(1):65.
pubmed: 33589598
pmcid: 7884415
doi: 10.1038/s41392-020-00440-z
Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, et al. Response to Neoadjuvant Therapy and Long-Term Survival in Patients With Triple-Negative Breast Cancer. J Clin Oncol. 2023;41(10):1809–15.
pubmed: 36989609
doi: 10.1200/JCO.22.02572
Nzigou Mombo B, Gerbal-Chaloin S, Bokus A, Daujat-Chavanieu M, Jorgensen C, Hugnot JP, et al. MitoCeption: Transferring Isolated Human MSC Mitochondria to Glioblastoma Stem Cells. J Vis Exp. 2017;120:55245.
Robey RW, Pluchino KM, Hall MD, Fojo AT, Bates SE, Gottesman MM. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat Rev Cancer. 2018;18(7):452–64.
pubmed: 29643473
pmcid: 6622180
doi: 10.1038/s41568-018-0005-8
Ambjørner SEB, Wiese M, Köhler SC, Svindt J, Lund XL, Gajhede M, et al. The Pyrazolo[3,4-d]pyrimidine Derivative, SCO-201, Reverses Multidrug Resistance Mediated by ABCG2/BCRP. Cells. 2020;9(3):613.
pubmed: 32143347
pmcid: 7140522
doi: 10.3390/cells9030613
Toyoda Y, Takada T, Suzuki H. Inhibitors of Human ABCG2: From Technical Background to Recent Updates With Clinical Implications. Front Pharmacol. 2019;10:208.
pubmed: 30890942
pmcid: 6411714
doi: 10.3389/fphar.2019.00208
Nedeljković M, Tanić N, Prvanović M, Milovanović Z, Tanić N. Friend or foe: ABCG2, ABCC1 and ABCB1 expression in triple-negative breast cancer. Breast Cancer. 2021;28(3):727–36.
pubmed: 33420675
doi: 10.1007/s12282-020-01210-z
Akman M, Belisario DC, Salaroglio IC, Kopecka J, Donadelli M, De Smaele E, et al. Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons. J Exp Clin Cancer Res. 2021;40(1):28.
pubmed: 33423689
pmcid: 7798239
doi: 10.1186/s13046-020-01824-3
Murota Y, Tabu K, Taga T. Requirement of ABC transporter inhibition and Hoechst 33342 dye deprivation for the assessment of side population-defined C6 glioma stem cell metabolism using fluorescent probes. BMC Cancer. 2016;16(1):847.
pubmed: 27814696
pmcid: 5097359
doi: 10.1186/s12885-016-2895-8