Signalni put Hedgehog povezan je s nastankom raznih tumora, ali točni mehanizmi djelovanje još nisu u potpunosti razjašnjeni. Fokus ovog istraživanja su tumori s mutacijama u genima BRAF ili NRAS, te njihov odgovor na inhibiciju signalnog puta Hedgehog. BRAF i NRAS nekanonički aktiviraju sva tri proteina GLI, ali točan slijed i djelovanje ovih interakcija još nisu razjašnjeni. Ovim projektom planiramo odrediti točne transkripcijske mete proteina GLI1, GLI2 i GLI3 u melanomima s različitim genetičkim podlogama: mutacijom u BRAF, mutacijom u NRAS, ili bez mutacije u ova dva gena. Stoga ćemo prvo provesti analizu ChIP-seq kako bismo odredili točne transkripcijske mete ovih proteina. Nakon toga uklonit ćemo gene za svaki od tih proteina („knock-out“) i sekvencirati transkriptome tih staničnih linija. Nakon izrade „knock-out“ linija, testirat ćemo ih nizom testova kako bismo odredili ulogu svakog od tri proteina GLI u tumorima ovisnim o mutacijama u BRAF/NRAS, te kako bismo razjasnili mehanizam njihovog djelovanja u melanomima. Kombiniranim tretmanima inhibitorima signalnog puta Hedgehog i specifičnim inhibitorima BRAF/NRAS, te izradom i testiranjem staničnih linija otpornih na te lijekove, pokazat ćemo postoji li pozitivan učinak za potencijalno liječenje melanoma. Sve ove analize pokazat će nam mogu li se proteini GLI ili njihovi ciljni geni koristiti kao potencijalni biomarkeri za melanom. Na kraju, u zadnjoj godini projekta, analizom potencijalnih biomarkera na kliničkim uzorcima, procijenit ćemo njihovu moguću primjenu u klinici. Ukratko, ovim projektom u planu je kompletna analiza GLI koda u melanomima ovisnim o BRAF/NRAS mutacijama, od određivanja transkripcijskih meta i pronalaženja molekularnih mehanizama do potencijalne primjene u klinici.

Radovi u časopisima

1. Piteša, Nikolina; Kurtović, Matea; Bartoniček, Nenad; Gkotsi, Danai S, Čonkaš, Josipa; Petrić, Tina; Musani, Vesna; Ozretić, Petar; Riobo-Del Galdo, Natalia A; Sabol, Maja. Signaling switching from Hedgehog-GLI to MAPK signaling potentially serves as a compensatory mechanism in melanoma cell lines resistant to GANT-61. Biomedicines (2023), 11, 1353.

2. Čonkaš, Josipa; Sabol, Maja; Ozretić, Petar. "Toxic masculinity": what is known about the role of androgen receptors in head and neck squamous cell carcinoma. International Journal of Molecular Sciences (2023), 24, 3766.

3. Kurtović, Matea; Piteša, Nikolina; Bartoniček, Nenad; Ozretić, Petar; Musani, Vesna; Čonkaš, Josipa; Petrić, Tina; King, Cecile; Sabol, Maja
RNA-seq and ChIP-seq Identification of Unique and Overlapping Targets of GLI Transcription Factors in Melanoma Cell Lines. Cancers, 14 (2022), 18; 4540. doi:10.3390/cancers14184540

4. Trnski, Diana; Sabol, Maja; Tomić, Sanja; Štefanac, Ivan; Mrčela, Milanka; Musani, Vesna; Rinčić, Nikolina; Kurtović, Matea; Petrić, Tina; Levanat, Sonja; Ozretić, Petar
SHH-N non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells. Scientific reports, 11 (2021), 1; 14880, 11. doi:10.1038/s41598-021-93971-6

5. Zubčić*, Vedran; Rinčić*, Nikolina; Kurtović, Matea; Trnski, Diana; Musani, Vesna; Ozretić, Petar; Levanat, Sonja; Leović, Dinko; Sabol, Maja
GANT61 and Lithium Chloride Inhibit the Growth of Head and Neck Cancer Cell Lines Through the Regulation of GLI3 Processing by GSK3beta.  // International journal of molecular sciences, 21 (2020), 6410, 13 doi:10.3390/ijms21176410

Sažeci sa skupova

1. Križanac, Marinela ; Leović, Matko ; Rinčić, Nikolina ; Trnski, Diana ; Musani, Vesna ; Ozretić, Petar ; Levanat, Sonja ; Zubčić, Vedran ; Leović, Dinko ; Sabol, Maja. Hedgehog-GLI signaling controls proliferation and invasiveness of head and neck squamous cell carcinoma. HDBMB2019 Crossroads in Life Sciences, 2019. (poster)

2. Rinčić, Nikolina ; Bartoniček, Nenad; Kurtović, Matea; Musani, Vesna; Trnski, Diana; Ozretić, Petar; Sabol, Maja. GLI transcription targets in melanoma cell lines. 45th FEBS Virtual Congress “Molecules of Life: Towards New Horizons“, 2021. (poster)

3. Rinčić, Nikolina ; Bartoniček, Nenad ; Kurtović, Matea ; Musani, Vesna ; Trnski, Diana ; Ozretić, Petar ; Sabol, Maja. Specific and overlapping GLI transcription targets in melanoma. EACR 2021 Virtual Congress, 2021. (poster)

4. Kurtović, Matea ; Rinčić, Nikolina ; , Trnski, Diana ; Musani, Vesna ; Ozretić, Petar ; Sabol, Maja. Generation of GLI1, GLI2 and GLI3 knock-out melanoma cell lines via CRISPR/Cas9 gene editing. EACR 2021 Virtual Congress, 2021. (poster)

5. Kurtović, Matea ; Rinčić, Nikolina ; Trnski, Diana ; Musani, Vesna ; Ozretić, Petar ; Sabol, Maja. CRISPR/Cas9 mediated knockout of GLI1, GLI2 and GLI3 genes in melanoma cell lines. 20th FEBS Young Scientists´Forum, 2021. (poster)

6. Kurtović, Matea ; Rinčić, Nikolina ; Trnski, Diana ; Musani, Vesna ; Ozretić, Petar ; Sabol, Maja. CRISPR/Cas9 mediated knockout of GLI1, GLI2 and GLI3 genes in melanoma cell lines. 45th FEBS Congress, 2021. (poster)

7. Petrić, Tina ; Trnski, Diana ; Kurtović, Matea ; Rinčić, Nikolina ; Musani, Vesna ; Ozretić, Petar ; Sabol, Maja. Hedgehog-GLI signaling pathway in 3D model of prostate cancer. Goodbye Flat Biology: Next Generation Cancer Models, 2021. (poster)

8. Piteša, Nikolina ; Bartoniček, Nenad ; Kurtović, Matea ; Musani, Vesna ; Trnski, Diana ; Ozretić, Petar ; Sabol, Maja. Genes for competing endogenous RNAs as targets of transcription factors GLI in melanoma cell lines. 5th Congress of the Serbian Association for Cancer Research (SDIR), 2021. (predavanje)

9. Čonkaš, Josipa ; Josić, Janja ; Piteša, Nikolina ; Kurtović, Matea ; Petrić, Tina ; Musani, Vesna ; Sabol, Maja ; Vugrinec, Ozren ; Leović, Dinko ; Ozretić, Petar. The role of androgen and androgen receptors in metastasis of head and neck tumors. 6. Simpozij studenata doktorskih studija PMF-a, 2022. (poster)

10. Piteša, N ; Kurtović, M ; Bartoniček, N ; Petrić, T ; Čonkaš, J ; Musani, V ; Ozretić, P ; Sabol, M. Hedgehog-GLI and MAPK signalling pathway activity in GANT61-resistant melanoma cells. 28th Congress of the European Association for Cancer Research (EACR 2022 Congress) "Innovative Cancer Science: Translating Biology to Medicine", 2022. (poster)

11. Kurtović, Matea ; Bartoniček, Nenad ; Piteša, Nikolina ; Ozretić, Petar ; Musani, Vesna ; Petrić, Tina ; Čonkaš, Josipa ; Sabol, Maja. RNA sequencing reveals unique and overlapping transcriptional targets of GLI1, GLI2 and GLI3 in melanoma cell lines. 28th Congress of the European Association for Cancer Research (EACR 2022 Congress) "Innovative Cancer Science: Translating Biology to Medicine", 2022. (poster)

12. Piteša, Nikolina ; Bartoniček, Nenad ; Kurtović, Matea ; Petrić, Tina ; Čonkaš, Josipa ; Musani, Vesna ; Ozretić, Petar ; Sabol, Maja. Primary cilia - a potential link between hedgehog- GLI and MAPK signaling in GANT61 -resistant melanoma cell lines. HDBMB22: From Science to Knowledge, 2022. (poster)

13. Čonkaš, Josipa ; Josić, Janja ; Piteša, Nikolina ; Kurtović, Matea ; Petrić, Tina ; Musani, Vesna ; Sabol, Maja ; Vugrinec, Ozren ; Leović, Dinko ; Ozretić, Petar. Membrane androgen receptor OXER1 indicates a potential role in metastasis of head and neck tumors. 6th Meeting of the Croatian Association for Cancer Research with International Participation: Targeting Cancer (HDIR-6), 2022. (poster)

14. Piteša, Nikolina ; Bartoniček, Nenad ; Kurtović, Matea ; Petrić, Tina ; Čonkaš, Josipa ; Musani, Vesna ; Ozretić, Petar ; Sabol, Maja. Signaling Switch from Hedgehog-GLI to MAPK Potentially Drives Primary Cilia Loss in NRAS Mutated GANT61-Resistant Melanoma Cell Line. 6th Meeting of the Croatian Association for Cancer Research with International Participation: Targeting Cancer (HDIR-6), 2022. (poster)

15. Petrić, Tina ; Kurtović, Matea ; Piteša, Nikolina ; Čonkaš, Josipa ; Musani, Vesna ; Ozretić, Petar ; Sabol, Maja. Hedgehog-GLI signaling pathway in 3D model of prostate cancer. HDBMB22: From Science to Knowledge, 2022. (poster)

16. Petrić, Tina ; Kurtović, Matea ; Piteša, Nikolina ; Čonkaš, Josipa ; Musani, Vesna ; Ozretić, Petar ; Sabol, Maja. 3D culture of prostate cancer as a model to study hedgehog-gli signaling pathway. 6th Meeting of the Croatian Association for Cancer Research with International Participation: Targeting Cancer (HDIR-6), 2022. (poster)

17. Petrić, Tina. Let's go 3D: the future of prostate cancer models. Digital science conference Kemomind, 2022. (predavanje)

18. Kurtović, Matea ; Piteša, Nikolina ; Bartoniček, Nenad ; Ozretić, Petar ; Musani, Vesna ; Petrić, Tina ; Čonkaš, Josipa ; Sabol, Maja. Unique and overlapping transcriptional targets of GLI1, GLI2 and GLI3 in melanoma cell lines. 6th Meeting of the Croatian Association for Cancer Research with International Participation: Targeting Cancer (HDIR-6), 2022. (poster)

19. Piteša, Nikolina ; Bartoniček, Nenad ; Kurtović, Matea ; Petrić, Tina ; Čonkaš, Josipa ; Musani, Vesna ; Ozretić, Petar ; Sabol, Maja. Characterization of GANT61 Resistant Cell Lines reveals new insights of Hedgehog-GLI and RAS/RAF/MAPK interplay in melanoma. EACR-Boehringer Ingelheim Drugging and Regulating the MAP Kinase Pathway, 2023. (poster)

20. Čonkaš, Josipa ; Josić, Janja ; Kranjčević, Jacqueline-Katrin ; Piteša, Nikolina ; Kurtović, Matea ; Musani, Vesna ; Sabol, Maja ; Vugrinec, Ozren ; Mumlek, Ivan ; Kvolik Pavić, Ana ; Zubčić, Vedran ; Leović, Dinko ; Ozretić, Petar. Correlation between the sex hormone receptors expression and demographic parameters in HNSCC patients 7. Simpozij studenata doktorskih studija PMF-a, 2023. (poster)

21. Piteša, Nikolina ; Kurtović, Matea ; Bartoniček, Nenad ; Gkotsi, Danai S, Čonkaš, Josipa ; Petrić, Tina ; Musani, Vesna ; Ozretić, Petar ; Riobo-Del Galdo, Natalia A ; Sabol, Maja. First Insights into the Characterization of GANT61 - Resistant Melanoma Cell Lines. Hedgehog signaling: From molecular structure to developmental biology and diseases, 2023. (poster)

22. Kurtović, Matea ; Bartoniček, Nenad ; Piteša, Nikolina ; Ozretić, Petar ; Musani, Vesna ; Čonkaš, Josipa ; Sabol, Maja. Unique and overlapping transcriptional targets of GLI1, GLI2 and GLI3 in melanoma cell lines. Hedgehog signaling: From molecular structure to developmental biology and diseases, 2023. (poster)

23. Sabol, Maja. Signalni putevi u melanomu: matičnost, plastičnost i rezistencija. 8. simpozij Apoptoza i novotvorine, 2023. (pozvano predavanje)

24. Piteša, Nikolina; Kurtović, Matea; Čonkaš, Josipa; Musani, Vesna; Ozretić, Petar; Sabol, Maja. The role of Hedgehog signaling pathway in plasticity, stemness and resistance of melanoma. 6th Congress of the Serbian Association for Cancer Research "SDIR-6" with international participation "From Collaboration to Innovation in Cancer Research", 2023. (pozvano predavanje)

25. Čonkaš, Josipa; Josić, Janja; Kranjčević, Jacqueline-Katrin; Milutin Gašperov, Nina; Piteša, Nikolina; Kurtović, Matea; Musani, Vesna; Sabol, Maja; Vugrinec, Ozren; Mumlek, Ivan et al. Expression Profile of Sex Hormone Receptors in Head and Neck Cancer: Unraveling Gender Disparities. 6th Congress of the Serbian Association for Cancer Research "SDIR-6" with international participation "From Collaboration to Innovation in Cancer Research", 2023. (poster)

Ocjenski radovi

1. Kurtović, Matea. Jedinstveni i preklapajući ciljni geni transkripcijskih faktora GLI1, GLI2 i GLI3 u melanomu čovjeka., 2023., doktorski rad, Sveučilište u Rijeci, Odjel za biotehnologiju, Rijeka (mentor: Maja Sabol)

2. Piteša, Nikolina. Interakcija signalnih puteva RAS/RAF/MAPK i Hedgehog-GLI u rezistenciji na lijekove u staničnim linijama melanoma čovjeka., 2023., doktorski rad, Sveučilište Josipa Jurja Strossmayera u Osijeku, Osijek (mentor: Maja Sabol)

3. Vučemilo, Nikolina. Uspostava trodimenzionalne sferoidne kulture stanica tumora glave i vrata., 2022., diplomski rad, Prirodoslovno-matematički fakultet, Biološki odsjek, Zagreb (mentor: Maja Sabol)

4. Brtan, Ana. Karakterizacija i validacija sojeva stanične linije melanoma dobivenih ugradnjom sekvence SHH u genom., 2021., diplomski rad, Prirodoslovno-matematički fakultet, Biološki odsjek, Zagreb (mentor: Maja Sabol)

5. Čonkaš, Josipa. Konstrukcija vektora za ekspresiju proteina SHH u staničnoj liniji melanoma čovjeka CHL-1., 2021., diplomski rad, Prirodoslovno-matematički fakultet, Biološki odsjek, Zagreb (mentor: Maja Sabol)

6. Šimatović, Domagoj. Uloga ekspresije p16 u karcinomima glave i vrata., 2021., diplomski rad, diplomski, Prirodoslovno-matematički fakultet, Zagreb (mentor: Vesna Musani)

7. Rinčić, Nikolina. Izrada "knock out" stanične linije za gen GLI1 primjenom sustava CRISPR/Cas9., 2018., diplomski rad, Prirodoslovno-matematički fakultet, Biološki odsjek, Zagreb (mentor: Maja Sabol)

Nagrade i priznanja

1. Čonkaš, Josipa: Godišnja nagrada Hrvatske udruge genetičkih inženjera Zoran Zgaga za najbolji diplomski rad u kojemu se primjenjuju metode genetičkog inženjerstva obranjen u akademskoj godini 2020./2021.

2. Rinčić, Nikolina: Godišnja nagrada Instituta Ruđer Bošković u 2020. g. za znanstveni rad pod nazivom "GANT61 and Lithium Chloride Inhibit the Growth of Head and Neck Cancer Cell Lines Through the Regulation of GLI3 Processing by GSK3beta"