Laboratory of Tumour Resistance

Laboratory is focused on the mechanisms of cancer resistance and iron metabolism

Group leader: Mgr. Jaroslav Truksa, Ph.D.

The major research topics investigated in the lab are:

  1. Understanding the molecular mechanisms underlying cancer resistance, proliferation and recurrence
  2. Describing the biology of cancer stem-like cells with particular interest in their iron metabolism
  3. Developing novel therapeutic approaches that affect cancer cells based on mitochondrial targeting and interference with iron metabolism
  4. Deciphering the molecular mechanisms that govern appropriate systemic iron metabolism

We cultivate and investigate the molecular profiles of cancer stem-like cells (CSCs) that grow as three dimensional „spheres“ and resemble more closely real tumours. CSCs show upregulation of the ABC transporters that confer resistance to commonly used anti-cancer drugs and exhibit marked changes in their iron metabolism, making them more susceptible to iron chelation.

We also elucidate molecular mechanisms that underlie tamoxifen-resistance in breast cancer cells and we have found increased level of mitochondrial reactive oxygen and altered mitochondrial structure and function in these cells. Importantly, we have also shown that high expression of miR-301a-3P in estrogen positive breast cancer cells results in inhibition of estrogen signalling, thus participating in the transition to tamoxifen resistance.

Based on the high iron requirements of cancer cells in general, we are developing novel promising iron chelators that are targeted to mitochondria as a crucial organelle that is responsible for the supply of both biologically utilized forms of iron, the FeS clusters and heme. The novel compounds show markedly profound cytostatic and cytotoxic effect on cancer cells while sparing non-malignant cells and reduce tumor growth in vivo.

We further focus on the normal sytemic iron homeostasis with particular interest in hepcidin, erythroferrone and matriptase-2 as critical molecules that govern the organismal response to iron deficiency, iron overload, hypoxia or enhanced erythropoiesis.

 

Jadhav Sukanya Balkrishna
Potomová Petra, Bc.
Sandoval Acuna Cristian Adrian
Torrealba Cárdenas Natalia Belén
Truksa Jaroslav, Mgr., Ph.D.
Vondráčková Michaela, Mgr.

2021

  • Krijt, J., Frýdlová, J., Gurieva, I., Přikryl, P., Báječný, M., Steinbicker, A., Vokurka, M., Truksa, J. (2021) "Matriptase-2 and Hemojuvelin in Hepcidin Regulation: In Vivo Immunoblot Studies in Mask Mice" IntJMolSci 22(5):2650

  • Sandoval-Acuna, C., Torrealba, N., Tomkova, V., Jadhav, S. B., Blazkova, K., Merta, L., Lettlova, S., Adamcova, M. K., Rosel, D., Brabek, J., Neuzil, J., Stursa, J., Werner, L., & Truksa, J. (2021). "Targeting mitochondrial iron metabolism suppresses tumor growth and metastasis by inducing mitochondrial dysfunction and mitophagy." Cancer Res. https://doi.org/10.1158/0008-5472.CAN-20-1628

2020

  • Fuentes-Retamal, S., C. Sandoval-Acuna, L. Peredo-Silva, D. Guzman-Rivera, M. Pavani, N. Torrealba, J. Truksa, V. Castro-Castillo, M. Catalan, U. Kemmerling, F. A. Urra and J. Ferreira (2020). "Complex Mitochondrial Dysfunction Induced by TPP(+)-Gentisic Acid and Mitochondrial Translation Inhibition by Doxycycline Evokes Synergistic Lethality in Breast Cancer Cells." Cells 9(2).

2019

  • Bajzikova, M., J. Kovarova, A. R. Coelho, S. Boukalova, S. Oh, K. Rohlenova, D. Svec, S. Hubackova, B. Endaya, K. Judasova, A. Bezawork-Geleta, K. Kluckova, L. Chatre, R. Zobalova, A. Novakova, K. Vanova, Z. Ezrova, G. J. Maghzal, S. M. Novais, M. Olsinova, L. Krobova, Y. J. An, E. Davidova, Z. Nahacka, M. Sobol, T. Cunha-Oliveira, C. Sandoval-Acuna, H. Strnad, T. C. Zhang, T. Huynh, T. L. Serafim, P. Hozak, V. A. Sardao, W. J. H. Koopman, M. Ricchetti, P. J. Oliveira, F. Kolar, M. Kubista, J. Truksa, K. Dvorakova-Hortova, K. Pacak, R. Gurlich, R. Stocker, Y. Q. Zhou, M. V. Berridge, S. Park, L. F. Dong, J. Rohlena and J. Neuzil (2019). "Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells." Cell Metabolism 29(2): 399-+.

  • Frydlova, J., D. W. Rogalsky, J. Truksa, E. Necas, M. Vokurka and J. Krijt (2019). "Effect of stimulated erythropoiesis on liver SMAD signaling pathway in iron-overloaded and iron-deficient mice." Plos One 14(4): e0215028.

  • Tomkova, V., C. Sandoval-Acuna, N. Torrealba and J. Truksa (2019). "Mitochondrial fragmentation, elevated mitochondrial superoxide and respiratory supercomplexes disassembly is connected with the tamoxifen-resistant phenotype of breast cancer cells." Free Radic Biol Med 143: 510-521.

2018

  • Frydlova, J., D. W. Rogalsky, J. Truksa, L. Traeger, A. U. Steinbicker, M. Vokurka and J. Krijt (2018). "Liver HFE protein content is posttranscriptionally decreased in iron-deficient mice and rats." American Journal of Physiology-Gastrointestinal and Liver Physiology 315(4): G560-G568.

  • Lettlova, S., V. Brynychova, J. Blecha, D. Vrana, M. Vondrusova, P. Soucek and J. Truksa (2018). "MiR-301a-3p Suppresses Estrogen Signaling by Directly Inhibiting ESR1 in ERalpha Positive Breast Cancer." Cell Physiol Biochem 46(6): 2601-2615.

2017

  • Blecha, J., S. M. Novais, K. Rohlenova, E. Novotna, S. Lettlova, S. Schmitt, H. Zischka, J. Neuzil and J. Rohlena (2017). "Antioxidant defense in quiescent cells determines selectivity of electron transport chain inhibition-induced cell death." Free Radic Biol Med 112: 253-266.

  • Dong, L. F., J. Kovarova, M. Bajzikova, A. Bezawork-Geleta, D. Svec, B. Endaya, K. Sachaphibulkij, A. R. Coelho, N. Sebkova, A. Ruzickova, A. S. Tan, K. Kluckova, K. Judasova, K. Zamecnikova, Z. Rychtarcikova, V. Gopalan, L. Andera, M. Sobol, B. Yan, B. Pattnaik, N. Bhatraju, J. Truksa, P. Stopka, P. Hozak, A. K. Lam, R. Sedlacek, P. J. Oliveira, M. Kubista, A. Agrawal, K. Dvorakova-Hortova, J. Rohlena, M. V. Berridge and J. Neuzil (2017). "Horizontal transfer of whole mitochondria restores tumorigenic potential in mitochondrial DNA-deficient cancer cells." Elife 6.

  • Frydlova, J., Z. Rychtarcikova, I. Gurieva, M. Vokurka, J. Truksa and J. Krijt (2017). "Effect of erythropoietin administration on proteins participating in iron homeostasis in Tmprss6-mutated mask mice." Plos One 12(10): e0186844.

  • Gurieva, I., J. Frydlova, Z. Rychtarcikova, M. Vokurka, J. Truksa and J. Krijt (2017). "Erythropoietin administration increases splenic erythroferrone protein content and liver TMPRSS6 protein content in rats." Blood Cells Mol Dis 64: 1-7.

  • Kralova, J., M. Kolar, M. Kahle, J. Truksa, S. Lettlova, K. Balusikova and P. Bartunek (2017). "Glycol porphyrin derivatives and temoporfin elicit resistance to photodynamic therapy by different mechanisms." Sci Rep 7: 44497.

  • Rohlenova, K., K. Sachaphibulkij, J. Stursa, A. Bezawork-Geleta, J. Blecha, B. Endaya, L. Werner, J. Cerny, R. Zobalova, J. Goodwin, T. Spacek, E. Alizadeh Pesdar, B. Yan, M. N. Nguyen, M. Vondrusova, M. Sobol, P. Jezek, P. Hozak, J. Truksa, J. Rohlena, L. F. Dong and J. Neuzil (2017). "Selective Disruption of Respiratory Supercomplexes as a New Strategy to Suppress Her2(high) Breast Cancer." Antioxid Redox Signal 26(2): 84-103.

  • Rychtarcikova, Z., S. Lettlova, V. Tomkova, V. Korenkova, L. Langerova, E. Simonova, P. Zjablovskaja, M. Alberich-Jorda, J. Neuzil and J. Truksa (2017). "Tumor-initiating cells of breast and prostate origin show alterations in the expression of genes related to iron metabolism." Oncotarget 8(4): 6376-6398.

2016

  • Frydlova, J., P. Prikryl, J. Truksa, L. L. Falke, X. Du, I. Gurieva, M. Vokurka and J. Krijt (2016). "Effect of Erythropoietin, Iron Deficiency and Iron Overload on Liver Matriptase-2 (TMPRSS6) Protein Content in Mice and Rats." Plos One 11(2): e0148540.

  • Tomasetti, M., F. Monaco, N. Manzella, J. Rohlena, K. Rohlenova, S. Staffolani, S. Gaetani, V. Ciarapica, M. Amati, M. Bracci, M. Valentino, J. Goodwin, M. Nguyen, J. Truksa, M. Sobol, P. Hozak, L. F. Dong, L. Santarelli and J. Neuzil (2016). "MicroRNA-126 induces autophagy by altering cell metabolism in malignant mesothelioma." Oncotarget 7(24): 36338-36352.

2015

  • Tan, A. S., J. W. Baty, L. F. Dong, A. Bezawork-Geleta, B. Endaya, J. Goodwin, M. Bajzikova, J. Kovarova, M. Peterka, B. Yan, E. A. Pesdar, M. Sobol, A. Filimonenko, S. Stuart, M. Vondrusova, K. Kluckova, K. Sachaphibulkij, J. Rohlena, P. Hozak, J. Truksa, D. Eccles, L. M. Haupt, L. R. Griffiths, J. Neuzil and M. V. Berridge (2015). "Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA." Cell Metabolism 21(1): 81-94.

  • Truksa, J., L. F. Dong, J. Rohlena, J. Stursa, M. Vondrusova, J. Goodwin, M. Nguyen, K. Kluckova, Z. Rychtarcikova, S. Lettlova, J. Spacilova, M. Stapelberg, M. Zoratti and J. Neuzil (2015). "Mitochondrially targeted vitamin E succinate modulates expression of mitochondrial DNA transcripts and mitochondrial biogenesis." Antioxid Redox Signal 22(11): 883-900.

  • Vondrusova, M., A. Bezawork-Geleta, K. Sachaphibulkij, J. Truksa and J. Neuzil (2015). "The effect of mitochondrially targeted anticancer agents on mitochondrial (super)complexes." Methods Mol Biol 1265: 195-208.

2014

  • Stapelberg, M., R. Zobalova, M. N. Nguyen, T. Walker, M. Stantic, J. Goodwin, E. A. Pasdar, T. Thai, K. Prokopova, B. Yan, S. Hall, N. de Pennington, S. R. Thomas, G. Grant, J. Stursa, M. Bajzikova, A. C. B. Meedeniya, J. Truksa, S. J. Ralph, O. Ansorge, L. F. Dong and J. Neuzil (2014). "Indoleamine-2,3-dioxygenase elevated in tumor-initiating cells is suppressed by mitocans." Free Radical Biology and Medicine 67: 41-50.

  • Tomasetti, M., L. Nocchi, S. Staffolani, N. Manzella, M. Amati, J. Goodwin, K. Kluckova, M. Nguyen, E. Strafella, M. Bajzikova, M. Peterka, S. Lettlova, J. Truksa, W. Lee, L. F. Dong, L. Santarelli and J. Neuzil (2014). "MicroRNA-126 suppresses mesothelioma malignancy by targeting IRS1 and interfering with the mitochondrial function." Antioxid Redox Signal 21(15): 2109-2125.

2013

  • Neuzil, J., L. F. Dong, J. Rohlena, J. Truksa and S. J. Ralph (2013). "Classification of mitocans, anti-cancer drugs acting on mitochondria." Mitochondrion 13(3): 199-208.

GACR: GA18-13103S, Truksa: Efficient killing of cancer cells via mitochondrial targeting of iron chelators. 2018-2020.

MEYS (NPUII): LQ1604, Truksa: BIOCEV - from Fundamental to Applied Research. 2016-2020.

GACR: GA16-12816S, Truksa: Addiction to oxidative phosphorylation in cancer and its relation to tumour initiation and therapy. 2016-2018.

Advanced Human Capital Program of the National Commision for Scientific and Technological Research (Chile): The effect of mitochondrially targeted polyhydroxybenzoates on breast cancer cells. 2015. Scholarship for staff exchange, University of Chile.

The Kellner Family Foundation (Principal Investigator Award): Truksa: Expression and regulation of multidrug resistance proteins in tumour-initiating cells (TICs). 2013-2016.

GACR: GA13-28830S, Truksa: Iron metabolism of the tumour-initiating cells. 2013-2017.

GACR: P305/12/1708, Truksa: Modulation of mitochondrial functions in cancer cells by the mitochondrially targeted vitamin E analogues. 2012-2014.