My group have been working in the field of integrin-mediated resistance of tumour cells to anticancer drugs for more than 10 years. Our interest in integrins started in 2004 when we found the expression of integrin αvβ3 in cisplatin resistant cell clone CA3ST, isolated upon multiple exposure to cisplatin of integrin αvβ3-negative human laryngeal carcinoma cell line HEp2, suggesting the role of this integrin in sensitivity to anticancer drugs (Ambriovic-Ristov et al. International Journal of Cancer, 2004). The second paper revealed a novel mechanism of αvβ3-mediated drug resistance to cisplatin, doxorubicin and mytomicin C mediated by increase of total glutathione content (Brozovic et al. Molecular Pharmacology, 2008). This year we published results of investigation of the resistance mechanism of tongue squamous carcinoma cells Cal27 with de novo integrin αvβ3 expression to anticancer drugs. We showed that integrin αvβ3 expression in Cal27 cells confers anticancer drug resistance through loss of pSrc(Y418) (Stojanovic et al., BBA Molecular Cell research, 2016). We have shown recently that β3 silencing in glioma cells represents a promising strategy to sensitize high-grade gliomas to temozolomide (TMZ) therapy. More specifically, β3 silencing suppresses DNA repair of TMZ-induced double strand brakes impairing homologous recombination (Christmann et al., Oncotarget, 2016).
We are currently investigating signalling pathways in tumour cells triggered by integrins and the potential of modulation of integrin expression for sensitisation of tumour cells to antitumour 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.
Different methods of molecular and cell biology and advanced light microscopy. Construction and use of adenovirus vectors in cell biology.
Methods for the isolation of adhesion complexes and identification of proteins using mass spectrometry
Ruščić J, Ambriović-Ristov A, Majhen D, Kolundžija S, Barut M, Benihoud K, Krajačić M. Manipulating adenoviral vector ion-exchange chromatography: Hexon versus fiber. J Sep Sci. 2016. in press
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, 2016 Jul 28. doi: 10.18632/oncotarget.10897.
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.
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.
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.