MICRORNA & MELANOMA · Dissecting intracellular signalling of melanoma invasion towards microRNA-based therapy
FP7 — People (Marie Curie Actions)
- Duration
- 2011-10-01 → 2015-09-30
- EU contribution
- €100,000
- Participants
- 1
- Scheme
- MC-CIG
Lines connect the coordinator with its partners.
Results in brief
Dissecting intracellular signalling of melanoma invasion towards microRNA-based therapy.
The most critical stage in initiation of melanoma metastasis is the radial to vertical growth transition, yet the triggers of this transition remain elusive. We suggest that the microenvironment drives melanoma metastasis independently of mutation acquisition. Here we examined the changes in microenvironment that occur during melanoma radial growth. We show that direct contact of melanoma cells with the remote epidermal layer triggers vertical invasion via Notch signaling activation, the latter serving to inhibit MITF function. Briefly, within the native Notch ligand-free microenvironment, MITF, the melanocyte lineage master regulator, binds and represses miR-222/221 promoter in an RBPJK-dependent manner. However, when radial growth brings melanoma cells into contact with distal differentiated keratinocytes that express Notch ligands, the activated Notch intracellular domain impairs MITF binding to miR- 222/221 promoter. This de-repression of miR-222/221 expression triggers initiation of invasion. Our findings may direct melanoma prevention opportunities via targeting specific microenvironments.
Data: CORDIS, © European Union
Project objective
Melanoma, a melanocytic neoplasm, is a highly lethal and treatment-refractory cancer. While progress has been made in deciphering the molecular underpinnings of melanoma, successful treatment for metastatic melanoma remains frustratingly uncommon. Complex phenotypes such as changes in cell morphology, motility, and invasiveness are rarely regulated by a single gene. Because a single microRNA (miR) may target thousands of genes, it is possible that altered expression of a single miR can regulate complex phenotypes. To identify miRs that regulate melanoma invasiveness, we performed a miR library screen for melanoma invasion potential. The melanoma-specific miR, miR-211, was the first highest hit which significantly decreased melanoma invasiveness. Our finding is the first description of an intronic miR that assumes a tumor suppressive function previously ascribed to its host gene (Levy et al Mol Cell 2010). In this study, we will further decipher miR-211 affect on melanoma invasion process by using an in-vivo model, we will compared our results with human clinical information to establish clinical relevance, we will identify new miRs that affect melanoma progression and we will dissect the cellular pathways regulated by these miRs and we will look for novel therapeutic approaches towards miR-based treatment of melanoma. Interestingly, both genes, miR-211 and its host gene are targets of MITF, the melanocyte lineage master regulator. We will therefore decipher the epigenetic changes that affect the transcriptional activity of MITF. We will globally study the cross talk between genome alteration and gene expression, while using MITF role in melanoma as a model in order to determine MITF dependent-epigenetic pattern.Our preliminary data suggest that modulating miR-211 dramatically affect melanoma invasion in-vivo. Our over-arching suggested will pave the way towards new pharmacologics approaches of suppressing melanomagenesis.
Original text from CORDIS.
Participants
- TEL AVIV UNIVERSITY · Tel AvivCoordinatorIsrael
Links
Data: CORDIS, © European Union