Dana Koludrovic

Bio: Dana Koludrovic is an academic researcher from French Institute of Health and Medical Research. The author has contributed to research in topics: Microphthalmia-associated transcription factor & Transcription factor. The author has an hindex of 5, co-authored 7 publications receiving 330 citations. Previous affiliations of Dana Koludrovic include University of Strasbourg.

Identification of a ZEB2-MITF-ZEB1 transcriptional network that controls melanogenesis and melanoma progression.

Abstract: Deregulation of signaling pathways that control differentiation, expansion and migration of neural crest-derived melanoblasts during normal development contributes also to melanoma progression and metastasis. Although several epithelial-to-mesenchymal (EMT) transcription factors, such as zinc finger E-box binding protein 1 (ZEB1) and ZEB2, have been implicated in neural crest cell biology, little is known about their role in melanocyte homeostasis and melanoma. Here we show that mice lacking Zeb2 in the melanocyte lineage exhibit a melanoblast migration defect and, unexpectedly, a severe melanocyte differentiation defect. Loss of Zeb2 in the melanocyte lineage results in a downregulation of the Microphthalmia-associated transcription factor (Mitf) and melanocyte differentiation markers concomitant with an upregulation of Zeb1. We identify a transcriptional signaling network in which the EMT transcription factor ZEB2 regulates MITF levels to control melanocyte differentiation. Moreover, our data are also relevant for human melanomagenesis as loss of ZEB2 expression is associated with reduced patient survival.

Transcription factor MITF and remodeller BRG1 define chromatin organisation at regulatory elements in melanoma cells

Abstract: Microphthalmia-associated transcription factor (MITF) is the master regulator of the melanocyte lineage. To understand how MITF regulates transcription, we used tandem affinity purification and mass spectrometry to define a comprehensive MITF interactome identifying novel cofactors involved in transcription, DNA replication and repair, and chromatin organisation. We show that MITF interacts with a PBAF chromatin remodelling complex comprising BRG1 and CHD7. BRG1 is essential for melanoma cell proliferation in vitro and for normal melanocyte development in vivo. MITF and SOX10 actively recruit BRG1 to a set of MITF-associated regulatory elements (MAREs) at active enhancers. Combinations of MITF, SOX10, TFAP2A, and YY1 bind between two BRG1-occupied nucleosomes thus defining both a signature of transcription factors essential for the melanocyte lineage and a specific chromatin organisation of the regulatory elements they occupy. BRG1 also regulates the dynamics of MITF genomic occupancy. MITF-BRG1 interplay thus plays an essential role in transcription regulation in melanoma.

MITF, the Janus transcription factor of melanoma

Abstract: Current models of melanoma propose that transition from the proliferative to the invasive stages of tumor development involves a dynamic and reversible switch in cell phenotype. The almost mutually exclusive proliferative and invasive phenotypes are defined by distinct gene expression signatures, which are themselves controlled by the level of functional MITF protein present in the cell. Recently, new signaling pathways and transcription factors that regulate MITF expression have been defined, and high throughput genomics have identified novel MITF target genes. MITF acts both as a transcription activator to promote expression of genes involved in cell cycle, but also as a transcriptional repressor of genes involved in invasion. A novel human germline mutation in MITF has been identified that blocks its sumoylation, thereby altering its transcriptional properties and conferring an increased risk of melanoma. These new studies depict an ever more complex function for MITF in melanoma.

Chromatin-Remodelling Complex NURF Is Essential for Differentiation of Adult Melanocyte Stem Cells

Abstract: MIcrophthalmia-associated Transcription Factor (MITF) regulates melanocyte and melanoma physiology. We show that MITF associates the NURF chromatin-remodelling factor in melanoma cells. ShRNA-mediated silencing of the NURF subunit BPTF revealed its essential role in several melanoma cell lines and in untransformed melanocytes in vitro. Comparative RNA-seq shows that MITF and BPTF co-regulate overlapping gene expression programs in cell lines in vitro. Somatic and specific inactivation of Bptf in developing murine melanoblasts in vivo shows that Bptf regulates their proliferation, migration and morphology. Once born, Bptf-mutant mice display premature greying where the second post-natal coat is white. This second coat is normally pigmented by differentiated melanocytes derived from the adult melanocyte stem cell (MSC) population that is stimulated to proliferate and differentiate at anagen. An MSC population is established and maintained throughout the life of the Bptf-mutant mice, but these MSCs are abnormal and at anagen, give rise to reduced numbers of transient amplifying cells (TACs) that do not express melanocyte markers and fail to differentiate into mature melanin producing melanocytes. MSCs display a transcriptionally repressed chromatin state and Bptf is essential for reactivation of the melanocyte gene expression program at anagen, the subsequent normal proliferation of TACs and their differentiation into mature melanocytes.

A POU3F2-MITF-SHC4 Axis in Phenotype Switching of Melanoma Cells

Abstract: Malignant melanoma is one of the most aggressive human cancers. Metastatic melanoma is highly resistant to genotoxic radiotherapy and chemotherapeutic treatments and patients have a median survival of under a year from diagnosis. As primary melanoma tumours can metastasise very early in tumour development (Chin et al., 2006), rapid diagnosis and curative surgery remain the best hopes for control of the disease. Early surgery that removes radial growth phase tumours that have not yet initiated vertical growth phase can be very effective and prevent further development. However, once the primary tumour has begun to invade the local epidermal and dermal environment treatment becomes much more complicated Why melanoma has such a high propensity to invade and metastasize is not well understood, but may be related to the developmental characteristics of the melanocyte lineage. Melanocytes derive from pluripotent neural crest cells as non-pigmented melanoblasts (Dupin et al., 2007; Dupin et al., 2006; Thomas and Erickson, 2008). During embryogenesis melanoblasts migrate via the dorso-lateral pathway to populate the basal layer of the epidermis and hair follicles, as well as a number of other sites including the inner ear and the heart (Yajima and Larue, 2008). The ability of transformed melanoma cells to rapidly invade and migrate away from the primary tumour perhaps reflects an inherent characteristic inherited from their embryonic state. Neural crest-derived cells are specified as melanoblasts by expression of MIcrophthalmiaassociated Transcription Factor (MITF), a basic helix-loop-helix transcription factor belonging to the MYC superfamily (Goding, 2000a; Goding, 2000b; Hemesath et al., 1994). The MITF locus encodes multiple isoforms generated by alternate splicing and use of internal promoters (Steingrimsson, 2008). The MITF-M isoform (hereafter designated simply as MITF) is produced specifically in the melanocyte lineage from an intronic promoter. MITF is required for melanoblast survival and differentiation of the retinal pigment epithelium (RPE) (Hou and Pavan, 2008; McGill et al., 2002). Consequently, MITF-null mice exhibit a white coat colour due to the loss of the melanocyte lineage and a small (microphthalmic) eye phenotype due to loss of the RPE (Hodgkinson et al., 1993; Hughes et al., 1993; Moore, 1995; Steingrimsson et al., 1994). In humans, mutation of the MITF gene is responsible for Waardenburg syndrome type 2 (WS2) ((Tassabehji et al., 1994), a syndrome characterised by pigmentary defects and hearing loss highlighting the important role of the

EMT in cancer

Abstract: Similar to embryonic development, changes in cell phenotypes defined as an epithelial to mesenchymal transition (EMT) have been shown to play a role in the tumorigenic process. Although the first description of EMT in cancer was in cell cultures, evidence for its role in vivo is now widely reported but also actively debated. Moreover, current research has exemplified just how complex this phenomenon is in cancer, leaving many exciting, open questions for researchers to answer in the future. With these points in mind, we asked four scientists for their opinions on the role of EMT in cancer and the challenges faced by scientists working in this fast-moving field.

The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer

Abstract: Metastasis is the major cause of cancer-associated death. Partial activation of the epithelial-to-mesenchymal transition program (partial EMT) was considered a major driver of tumour progression from initiation to metastasis. However, the role of EMT in promoting metastasis has recently been challenged, in particular concerning effects of the Snail and Twist EMT transcription factors (EMT-TFs) in pancreatic cancer. In contrast, we show here that in the same pancreatic cancer model, driven by Pdx1-cre-mediated activation of mutant Kras and p53 (KPC model), the EMT-TF Zeb1 is a key factor for the formation of precursor lesions, invasion and notably metastasis. Depletion of Zeb1 suppresses stemness, colonization capacity and in particular phenotypic/metabolic plasticity of tumour cells, probably causing the observed in vivo effects. Accordingly, we conclude that different EMT-TFs have complementary subfunctions in driving pancreatic tumour metastasis. Therapeutic strategies should consider these potential specificities of EMT-TFs to target these factors simultaneously.

Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma.

Abstract: Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas.