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GLIcode - Differential regulation of the GLI code in BRAF/NRAS driven tumors

Principal investigator

Category
Projekti Hrvatske zaklade za znanost
Project code
IP-2018-01-4889
Finance value
998.054,00
HRK
Start date
Jan 1st 2019
End date
Dec 31st 2022
Status
Active
GLIcode - Differential regulation of the GLI code in BRAF/NRAS driven tumors

The Hedgehog signaling pathway has been implicated in development of various tumors, but the exact roles and molecular mechanisms are still not understood. The focus of this research are the tumors harboring BRAF or NRAS mutations, and their differential response to Hedgehog pathway inhibition. Both BRAF and NRAS non-canonically activate the three GLI proteins, but the activity and interplay of this interaction is still unclear. With this project we propose to determine the exact transcriptional targets of GLI1, GLI2 and GLI3 proteins in melanoma with different genetic backgrounds, either harboring a BRAF mutation, a NRAS mutation, or no mutation in these two genes. For this purpose, we will first perform ChIP-seq to determine the transcriptional targets, then knock-out each of the three GLI proteins and sequence the transcriptomes of the knock-out cell lines. After the knock-outs have been generated, a series of cell assays will be performed to determine the role of each of the three GLI proteins in BRAF/NRAS dependent tumors, and to elucidate the mechanism of their action in melanoma. Combined treatments with Hedgehog inhibitors and specific BRAF/NRAS inhibitors, followed by generation and testing of resistant cell lines, will demonstrate if there is a potential benefit in the clinical management of melanoma. Finally, in the final year of the project, a set of clinical samples will be analyzed for these potential biomarkers to determine their possible use in the clinic. In summary, this project plans a complete analysis of the GLI code in BRAF/NRAS dependent melanoma, from determining the transcriptional targets and finding molecular mechanisms, to potential translation to the clinic.

Other associates

Vesna Musani, dr.sc.

Senior research associate
Tel:
+385 1 457 1292
Interni broj:
1849

Petar Ozretić, dr.sc.

Research associate
Tel:
+385 1 457 1292
Interni broj:
1849

Diana Trnski, dr.sc.

Postdoctoral researcher
Interni broj:
1849
1512

Nikolina Rinčić

Assistant
Tel:
457129
Interni broj:
1849

Matea Kurtović

Assistant
Tel:
+385 1 457 1292
Interni broj:
1849

External Associates:

Nenad Bartoniček, MD, Garvan Institute of Medical Research

Prim. Sanja Poduje, MD, KBCSM

Prof. Majda Vučić, MD, PhD, KBCSM

Consultants:

Sonja Levanat

S

L

Tel:
+385 1 457 1267
Interni broj:
1551

Neda Slade, dr.sc.

Head of laboratory
Tel:
+385 1 456 0926
Interni broj:
1511

Academician Mirna Šitum, MD, PhD, KBCSM

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