Research objectives:

1. Integrin-mediated signalling pathways in tumour cells upon exposure to antitumour drugs and metastasis.
2. Molecular mechanisms of drug resistance in tumour cells with an emphasis on the role of miRNA and integrins in these processes.
3. Newly synthesised compounds as potential antitumor drugs.
4. Adenovirus vectors as tools for gene transfer and vaccination.

Research groups:

Ambriović Ristov Group

Group Ambriović-Ristov investigates signalling pathways in tumour cells triggered by integrins and the potential of modulation of integrin expression for sensitisation of tumour cells to antitumor drugs. In addition, we study the role of integrins in cell migration and invasion. We are interested in focal adhesions, defined as a type of adhesive contact between the cell and extracellular matrix, their composition, formation and evolution in living cells during spreading or migration.

Brozović Group

The major problems of successful chemotherapy are development of drug resistance and side effects. Brozovic group is focused on molecular mechanisms involved in drug resistance of tumour cells especially on the role of miRNAs and correlation between epithelial-mesenchymal transition and drug resistance. Further, in order to improve the success of chemotherapy, Brozovic group is investigating the biological effects of newly synthesised compounds, the organometallic complexes.

Majhen Group

Adenovirus based vectors have potential translational and commercial values and are currently studied as vectors for gene transfer and vaccination. In Majhen group we study the basic biology of adenoviral vectors, namely adenovirus type 5 and 26. The main objective of our study is finding a link between binding of the adenoviral vector to the receptor on the cell surface, its intracellular trafficking and induction of immune response of the infected cell. Our research interest is also retargeting of adenoviral vectors toward molecule of interest and studying intracellular trafficking of retargeted adenoviral vectors.

Featured publications

2021

• De Las Rivas J, Brozovic A, Izraely S, Casas-Pais A,  Witz IP, Figueroa A. Cancer drug resistance induced by EMT: novel therapeutic strategies. Archives of Toxicology, 95, 2279-2297, 2021.
• Schijns V, Majhen D, van der Ley P, Thakur A, Summerfield A, Berisio R, Nativi C, Fernández-Tejada A, Alvarez-Dominguez C, Gizurarson S, Zamyatina A, Molinaro A, Rosano C, Jakopin Ž, Gursel I, McClean S. Rational Vaccine Design in Times of Emerging Diseases: The Critical Choices of Immunological Correlates of Protection, Vaccine Antigen and Immunomodulation. Pharmaceutics. 2021 Apr 6;13(4):501. doi: 10.3390/pharmaceutics13040501.
• Tadijan A, Samaržija I, Humphries JD, Humphries MJ, Ambriović-Ristov A. KANK family proteins in cancer. Int J Biochem Cell Biol. 2021 Feb;131:105903. doi: 10.1016/j.biocel.2020.105903. Epub 2020 Dec 10.

2020

• Šmidlehner T, Košćak M, Božinović K, Majhen D, Schmuck C, Piantanida I. Fluorimetric and CD recognition between Various ds-DNA/RNA Depends on a Cyanine Connectivity in Cyanine-guanidiniocarbonyl-pyrrole Conjugate, Molecules 2020, 25(19), 4470. doi: 10.3390/molecules25194470
• Božinović K*, Nestić D*, Centa UG, Ambriović-Ristov A, Dekanić A, de Bisschop L, Remškar M, Majhen D. In-vitro toxicity of molybdenum trioxide nanoparticles on human keratinocytes. Toxicology. 2020 Sep 4:152564. doi: 10.1016/j.tox.2020.152564. *equal contribution
• Samaržija I, Dekanić A, Humphries JD, Paradžik M, Stojanović N, Humphries MJ, Ambriović-Ristov A. Integrin Crosstalk Contributes to the Complexity of Signalling and Unpredictable Cancer Cell Fates. Cancers (Basel). 2020 Jul 15;12(7):1910. doi:10.3390/cancers 12071910.
• Erin N, Grahovac J, Brozovic A, Efferth T. Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance. Drug Resistance Updates. 53:100715, 2020, Invited review
• Torić J, Brozovic A^#, Baus Lončar M, Jakobušić Brala C, Karković Marković A, Benčić Đ, Barbarić M^#. Biological Activity of Phenolic Compounds in Extra Virgin Olive Oils through Their Phenolic Profile and Their Combination with Anticancer Drugs Observed in Human Cervical Carcinoma and Colon Adenocarcinoma Cells. Antioxidants (Basel). 9(5):453, 2020. ^#corresponding authors
• Paradžik M, Humphries JD, Stojanović N, Nestić D, Majhen D, Dekanić A, Samaržija I, Sedda D, Weber I, Humphries MJ, Ambriović-Ristov A. KANK2 Links αVβ5 Focal Adhesions to Microtubules and Regulates Sensitivity to Microtubule Poisons and Cell Migration. Frontiers in Cell and Developmental Biology. 8:125, 2020.
• Hulin-Curtis SL, Davies JA, Nestić D, Bates EA, Baker AT, Cunliffe TG, Majhen D, Chester JD, Parker AL. Identification of folate receptor α (FRα) binding oligopeptides and their evaluation for targeted virotherapy applications. Cancer Gene Ther. 2020 Jan 6. doi: 10.1038/s41417-019-0156-0.

2018-2019

• Kralj J*, Bolje A*, Stupin Polančec D, Gržan T, Tupek A, Steiner I, Stojanović N, Hohloch S, Urankar D, Osmak M, Sarkar B^#, Brozovic A^#, Košmrlj J^#. Half-Sandwich Ir(III) and Os(II) complexes of pyridyl-mesoionic carbenes as potential anticancer drugs. Organometallics. 38:4082-4092, 2019. *equal contribution, ^#corresponding authors, the Editors of Organometallics selected our graphics for the Supplementary Cover Art, which you can see at http://pubs.acs.org/toc/orgnd7/38/21. Additional facts about this work are located at https://www.irb.hr/Novosti/Rad-molekularnih-biologa-objavljen-u-uglednom-casopisu-Organometallics
• Assaraf YG, Brozovic A, Gonçalves AC, Jurkovicova D, Line A, Machuqueiro M, Saponara S, Sarmento AB, Xavier CPR, Vasconcelos MH. The multi-factorial nature of clinical multidrug resistance in cancer. Drug Resistance Updates. 46:100645, 2019. Invited review; Portuguese Association of Cancer Research selected this work to be highlighted on their website https://www.aspic.pt/en/multi-factorial-nature-clinical-multidrug-resistance-cancer#.XhhsFvzgo2w.
• Tomicic MT, Steigerwald C, Rasenberger B, Brozovic A, Christmann M. Functional mismatch repair and inactive p53 drive sensitization of colorectal cancer cells to irinotecan via the IAP antagonist BV6. Archives of Toxicology. 93:2265-2277, 2019.
• Matić J, Šupljika F, Tandarić T, Dukši M, Piotrowski P, Vianello R, Brozovic A, Piantanida I, Schmuck C, Stojković MR. DNA/RNA recognition controlled by the glycine linker and the guanidine moiety of phenanthridine peptides. International Journal of Biological Macromolecules. 134:422-434, 2019.
• Pernar M*, Kokan Z*, Kralj J, Glasovac Z, Tumir L-M, Piantanida I, Eljuga D, Turel I, Brozovic A^#, Kirin SI^#. Organometallic ruthenium(II)-arene complexes with triphenylphosphine amino acid bioconjugates: Synthesis, characterization and biological properties. Bioorganic Chemistry. 87:432-446, 2019. *equal contribution, ^#corresponding authors
• Nestić D, Uil TG, Ma J, Roy S, Vellinga J, Baker AH, Custers J, Majhen D. αvβ3 Integrin is Required for Efficient Infection of Epithelial Cells with Human Adenovirus Type 26. Journal of Virology. 93(1)e01474-18, 2018.
• Stojanović N*, Dekanić A*, Paradžik M, Majhen D, Ferenčak K, Ruščic J, Bardak I, Supina C, Tomičić MT, Christmann M, Osmak M, Ambriović-Ristov A. Differential effects of integrin αv knockdown and cilengitide on sensitisation of triple- negative breast cancer and melanoma cells to microtubule poisons. Molecular Pharmacology. 94(6)1334-1351, 2018. *equal contribution
• Grienke U, Radić Brkanac S, Vujčić V, Urban E, Ivanković S, Stojković R, Rollinger JM, Kralj J, Brozovic A*, Radić Stojković M*. Biological activity of flavonoids and rare sesquiterpene lactones isolated from Centaurea ragusina L. Frontiers in Pharmacology. 9:972, 2018. *corresponding authors
• Brozovic A. Opinion letter regarding the article Arch Toxicol https://doi.org/10.1007/s00204-018-2240-x. Archives of Toxicology. 92:3241, 2018.
• Pinterić M, Podgorski II, Sobočanec S, Popović Hadžija M, Paradžik M, Dekanić A, Marinović M, Halasz M, Belužić R, Davidović G, Ambriović Ristov A, Balog T. De novo expression of transfected sirtuin 3 enhances susceptibility of human MCF-7 breast cancer cells to hyperoxia treatment. Free Radical Research. 52:627-684, 2018.

2016-2017

• Bressy C, Majhen D, Raddi N, Jdey W, Cornilleau G, Zig L, Guirouilh-Barbat J, Lopez BS, Bawa O, Opolon P, Grellier E, Karim B. Combined therapy of colon carcinomas with an oncolytic adenovirus and valproic acid. Oncotarget. 2017; 8:97344-97360.
• Kokan Z, Perić B, Kovačević G, Brozovic A, Metzler-Nolte N, Kirin SI. Cis- vs. trans- square-planar palladium(II) and platinum(II) complexes with triphenylphosphine amino acid bioconjugates. European Journal of Inorganic Chemistry. 33:3928-3937, 2017.
• Hayek SS, Koh KH, Grams ME, Wei C, Ko Y-A, Li J, Samelko B, Lee H, Dande RR, Lee HW, Hahm E, Peev V, Tracy M, Tardi NJ, Gupta V, Altintas MM, Garborcauskas G, Stojanović N, Winkler CA, Lipkowitz MS, Tin A, Inker LA, Levey AS, Zeier M, Freedman BI, Kopp JB, Skorecki K, Coresh J, Quyyumi AA, Sever S, Reiser J. A tripartite complex of suPAR, APOL1 risk variants and αvβ3 integrin on podocytes mediates chronic kidney disease. Nature Medicine. 23:945-953, 2017.
• Teofilović NK, Bihi M, Stojković MR, Tumir LM, Ester K, Kralj M, Majhen D, Oršolić N, Lepur A, Vrbanec D, Markotić A, Dembić Z, Weber AN, Piantanida I, Vugrek O, Diken M, Knežević J. 1-ethyl-3-(6-methylphenanthridine-8-il) urea modulates TLR3/9 activation and induces selective pro-inflammatory cytokine expression in vitro. Bioorg Med Chem Lett. 2017 Feb 20. pii: S0960-894X(17)30181-6. doi: 10.1016/j.bmcl.2017.02.048.
• Brozovic A. The relationship between platinum drug resistance and epithelial-mesenchymal transition. Archives of Toxicology, 91:605–619, 2017. Invited review; RBI Annual Award for the best paper in 2017
• Christmann M., Diesler K., Majhen D., Steigerwald C., Berte N., Freund H., Stojanović N., Kaina B., Osmak M., Ambriović-Ristov A.^#, Tomicic MT^#. Integrin αVβ3 silencing sensitizes malignant glioma cells to temozolomide by suppression of homologous recombination repair. Oncotarget. 8(17):27754-27771, 2017. ^#corresponding authors
• Vajs J., Proud C., Brozovic A., Gazvoda M., Lloyd A., Roper D.I., Osmak M., Košmrlj J., Dowson C.G. Diaryltriazenes as antibacterial agents against methicillin resistant Staphylococcus aureus (MRSA) and Mycobacterium smegmatis. European Journal of Medicinal Chemistry. 127:223-234, 2016.
• Ruščić J*, Ambriović-Ristov A*, Majhen D, Kolundžija S, Barut M, Benihoud K, Krajačić M. Manipulating adenoviral vector ion-exchange chromatography: Hexon versus fiber. Journal of Separation Science. 39(22):4299-4304, 2016. *equal contribution
• Stojanović N., Brozovic A., Majhen D., Bosnar M.H., Fritz G., Osmak M., Ambriović-Ristov A. Integrin αvβ3 expression in tongue squamous carcinoma cells Cal27 confers anticancer drug resistance through loss of pSrc(Y418). Biochimica et Biophysica Acta. 1863(8):1969-78, 2016. N. Stojanović je za ovaj rad dobila sljedeće nagrade: Nagrada "Željko Trgovčević" za 2016. god.; Godišnja nagrada Društva sveučilišnih nastavnika i drugih znanstvenika u Zagrebu mladim znanstvenicima i umjetnicima u 2016. god.; Godišnja nagrada Zavoda za molekularnu biologiju Instituta Ruđer Bošković za 2016. god. u kategoriji za najbolji znanstveni rad zaposlenika koji je u trenutku objave rada imao doktorat znanosti
• Sobočanec, S., Filić, V., Matovina, M., Majhen, D., Šafranko, ŽM., Hadžija, MP., Krsnik, Ž., Kurilj, AG., Šarić, A., Abramić, M., Balog, T. Prominent role of exopeptidase DPP III in estrogen-mediated protection against hyperoxia in vivo. Redox Biology. 8: 149-159, 2016. 
• Steiner I.*, Stojanović N.*, Bolje A., Brozovic A., Polančec D., Ambriović-Ristov A., Radić Stojković M., Piantanida I, Eljuga D., Košmrlj J., Osmak M. Discovery of ‘click’ 1,2,3-triazolium salts as potential anticancer drugs. Radiology and Oncology. 19;50(3):280-288, 2016. *equal contribution

2014-2015

• Brozovic A., Duran G.E., Wang Y.C., Francisco B.E., Sikic B.I. The miR-200 family differentially regulates sensitivity to paclitaxel and carboplatin in human ovarian carcinoma OVCAR-3 and MES-OV cells. Molecular Oncology. 9(8):1678-93., 2015.
• Vajs J.*, Steiner I.*, Brozovic A.*, Pevec A., Ambriović-Ristov A., Matković M., Piantanida I., Urankar D., Osmak M., Košmrlj J. The 1,3-diaryltriazenido(p-cymene)ruthenium(II) complexes with a high in vitro anticancer activity. J Inorg Biochem. 153:42-8. 2015. *equal contribution
• Krüger K., Thomale J., Stojanovic N., Osmak M., Henninger C., Bormann S., Fritz G. Platinum-induced kidney damage: Unraveling the DNA damage response (DDR) of renal tubular epithelial and glomerular endothelial cells following platinum injury. Biochimica et Biophysica Acta. 1853: 685-698, 2015.
• Murati T., Šimić B., Brozovic A., Kniewald J., Miletić Gospić A., Bilandžić N., Kmetič I. PCB 77 action in ovary cells--toxic effects, apoptosis induction and cell cycle analysis. Toxicology Mechanisms and Methods. 25(4): 302-11., 2015.
• Majhen D., Calderon H., Chandra N., Fajardo C.A., Rajan A., Alemany R., Custers J. Adenovirus-based vaccines for fighting infectious diseases and cancer: progress in the field.Human Gene Therapy. 25, 301-317, 2014.
• Majhen D., Stojanović N., Vukić D., Pichon C., Leduc C., Osmak M., Ambriović-Ristov A. Increased Adenovirus Type 5 Mediated Transgene Expression Due to RhoB Down-regulation, PLoS One. 9(1): e86698, 2014.
• Moisan F., Francisco E.B., Brozovic A., Duran G.E., Wang Y.C., Chaturvedi S., Seetharamb S., Snyder L.A., Doshi P., Sikic B.I. Enhancement of Paclitaxel and Carboplatin Therapies by CCL2 Blockade in Ovarian Cancers. Molecular Oncology. 8: 1231-1239, 2014.
• Rak S., De Zan T., Štefulj J., Kosović M., Gamulin O., Osmak M. FTIR spectroscopy reveals lipid droplets in drug resistant laryngeal carcinoma cells through detection of increased ester vibrational bands intensity. Analyst. 139, 13: 3407-3415, 2014.
• Sommer M., Kureljak P., Urankar D., Schweinfurth D., Stojanović N., Bubrin M., Gazvoda M., Osmak M., Sarkar B., Košmrlj J. Combining [Arene–Ru] with Azocarboxamide to Generate a Complex with Cytotoxic Properties. Chemistry: A European Journal, Communication. 20: 17296-17299, 2014.
• Vellinga J., Smith J.P., Lipiec A., Majhen D., Lemckert A., van Ooij M., Ives P., Yallop C., Custers J., Havenga M. Challenges in manufacturing adenoviral vectors for global vaccine product deployment. Human Gene Therapy. 25: 318-327, 2014.

2012-2013

• Brozovic A., Vuković L., Polančac D.S., Arany I., Köberle B., Fritz G., Fiket Z., Majhen D., Ambriović-Ristov A., Osmak M. Endoplasmic reticulum stress is involved in the response of human laryngeal carcinoma cells to carboplatin but is absent in carboplatin-resistant cells. PLoS One. 8(9): e76397, 2013.
• Rak S., Čimbora-Zovko T., Gajski G., Dubravčić K., Domijan A., Delaš I., Garaj-Vrhovac V., Batinić D.,  Sorić J., Osmak M. Carboplatin resistant human laryngeal carcinoma cells are cross resistant to curcumin due to reduced curcumin accumulation. Toxicology In Vitro. 27, 2; 523-532, 2013.
• Watanabe S., De Zan T., Ishizaki T., Yasuda S., Kamijo H., Yamada D., Aoki T., Kiyonari H., Kaneko H., Shimizu R., Yamamoto M., Goshima G., Narumiya S. Loss of a Rho-regulated actin nucleator, mDia2, impairs cytokinesis during mouse fetal erythropoiesis. Cell Reports. 20135:926-932, 2013. 
• Watanabe S., De Zan T., Ishizaki T., Narumiya S. Citron kinase mediates transition from constriction to abscission through its coiled-coil domain. Journal of Cell Science. 126:1773-84, 2013.
• Gabrilovac J., Čupić B., Zapletal E., Brozović A. IFN-γ up-regulates kappa opioid receptors (KOR) on murine macrophage cell line J774. Journal of Neuroimmunology. 245, 1/2; 56-65, 2012.
• Majhen D., Richardson J., Vukelić B., Dodig I., Cindrić M., Benihoud K., Ambriović-Ristov A. The disulfide bond of an RGD4C motif inserted within the HI loop of the adenovirus type 5 fiber protein is critical for retargeting to αv-integrins. Journal of Gene Medicine. 14(12): 788-797, 2012.
• Osmak M. Statins and cancer: Current and future prospects. Cancer Letters. 324, 1; 1-12, 2012.

2010-2011

• Čimbora-Zovko T., Brozović A., Piantanida I., Fritz G., Virag A., Alič B., Majce V., Kočevar M., Polanc S., Osmak M. Synthesis and biological evaluation of 4-nitro-substituted 1, 3-diaryltriazenes as a novel class of potent antitumor agents. European Journal of Medicinal Chemistry. 46: 2971-2983, 2011.
• Gabrilovac J., Čupić B.,Živković E., Horvat L., Majhen D. Expression, regulation and functional activities of aminopeptidase N (EC 3.4.11.2 ; APN ; CD13) on murine macrophage J774 cell line. Immunobiology. 216, 1/2; 132-144, 2011.
• Helbig L., Damrot J., Hülsenbeck J., Köberle B., Brozović A., Osmak M., Fiket Ž., Kaina B., Fritz G. Late activation of stress-activated protein kinases/C-JUN-N- terminal kinases triggered by cisplatin-induced DNA damage repair defective cells. The Journal of Biological Chemistry. 286, 15; 12991-13001, 2011.
• Majhen D., Stojanović N., Špeljko T., Brozović A., De Zan T., Osmak M., Ambriović-Ristov A. Increased expression of the coxsackie and adenovirus receptor downregulates alpha v beta 3 and alpha v beta 5 integrin expression, reduces cell adehesion and migration. Life Sciences. 89: 241-249, 2011.
• Brozovic A., Ambriović-Ristov A., Osmak M. The relationship between cisplatin-induced reactive oxygen species, glutathione and BCL-2, and resistance to cisplatin. Critical Reviews in Toxicology. 40(4): 347-359, 2010.
• Majhen D*, Brozovic A*, Buger T, Gabrilovac J, Osmak M, Ambriović-Ristov A. Vincristine-resistant human laryngeal carcinoma cells demonstrate increased Rous sarcoma virus promoter activity. Life Sciences. 87(15-16):468-474, 2010.  *equal contribution
• Burja B., Čimbora-Zovko T., Tomić S., Jelušić T., Kočevar M., Polanc S., Osmak M. Pyrazolone-fused combretastatins and their precursors: synthesis, cytotoxicity, antitubulin activity and molecular modeling studies. Bioorganic & Medicinal Chemistry. 18: 2375-2387, 2010.
• Cimbora-Zovko T., Fritz G., Mikac N., Osmak M. Downregulation of RhoB GTPase confers resistance to cisplatin in human laryngeal carcinoma cells. Cancer Letters.  295:182-190, 2010.

2008-2009

• Brozović A., Damrot J., Tsaryk R., Helbig L., Nikolova T., Hartig C., Osmak M., Roos W., Kaina B., Fritz G. Cisplatin sensitivity is related to late DNA damage processing and checkpoint control rather than to the early DNA damage response. Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. 670, 1-2; 32-41, 2009.
• Majhen D., Nemet J., Richardson J., Gabrilovac J., Hajsig M., Osmak M., Eloit M., Ambriović-Ristov A. Differential role of αvβ3 and αvβ5 integrins in internalization and transduction efficacies of wild type and RGD4C fiber-modified adenoviruses. Virus Research. 139(1): 64-73, 2009.
• Brozović A., Majhen D, Roje V., Mikac N., Jakopec S., Fritz G., Osmak M., Ambriović-Ristov A. αvβ3 integrin mediated drug resistance in human laryngeal carcinoma cells is caused by glutathione dependent elimination of drug induced reactive oxidative species. Molecular Pharmacology. 74: 298-306, 2008.

2006-2007

• Brozović A., Osmak M. Activation of mitogen-activated protein kinases by cisplatin and their role in cisplatin-resistance. Cancer Letters. 251 (2007), 1; 1-16, 2007.
• Čimbora-Zovko T., Ambriović-Ristov A.; Lončarek J., Osmak M.: Altered cell-cell adhesion in cisplatin-resistant human carcinoma cells: A link between b-catenin/plakoglobin ratio and cisplatin resistance. European Journal of Pharmacology. 558: 27-36, 2007.
• Zisowsky J., Koegel S., Leyers S., Devarakonda K., Kassack M., Osmak M., Jaehde U. Relevance of drug uptake and efflux for platinum sensitivity of tumour cells. Biochemical Pharmacology. 73, 2; 298-307, 2007.
• Jakopec S., Dubravčić K., Polanc S., Košmrlj J., Osmak M.: Diazene JK-274 induces apoptosis-like cell death in human cervical carcinoma cells. Toxicology In Vitro. 20:217-226, 2006.
• Majhen D., Ambriović-Ristov, A. Adenoviral vectors-how to use them in cancer gene therapy, Virus Research. 119: 121-133, 2006.
• Majhen D., Gabrilovac J., Eloit M., Richardson J., Ambriović-Ristov A. Disulfide bond formation in NGR fiber-modified adenovirus is essential for retargeting to aminopeptidase N. Biochemical and Biophysical Research Communications. 348: 278-287, 2006.