The incidence and mortality of melanoma, the most aggressive form of skin cancer, are rapidly increasing worldwide. The abysmal survival rates stem from the highly metastatic and chemoresistant behavior of these tumors, but the molecular basis of this aggressive phenotype remains unclear. We and others have shown that melanoma cells display stem-cell-like properties: they often express developmental genes, have multi-differentiation potential, and seem to evoke the migratory nature of neural crest stem cells from which melanocytes arise. These observations suggest that alterations in developmental programs within the melanocytic lineage might underlie the malignant evolution of these cells into metastatic melanoma. In fact, metastasis can be conceived as a normal migration program gone awry, and our laboratory has found that a particular cluster of miRNAs (which in general regulate development, differentiation, and tissue homeostasis) is frequently overexpressed in melanoma cell lines and tissues. We have shown that this miR-183-96-182 cluster promotes migration in vitro and metastasis in vivo in part by controlling the expression of MITF, a master regulator of melanocyte differentiation. Intriguingly, we have also found that miR-183-96-182 is highly expressed in embryonic stem cells (ES), and is silenced during in vitro melanocyte differentiation, inversely correlating with MITF levels. Furthermore, our preliminary studies indicate that histone acetylation and Krupple-like factor-4 (KLF4), a canonical pluripotency transcription factor, govern miR-183-96-182 expression in both hESCs and melanoma cells. We hypothesize that miR-183-96-182 repression is required for melanocyte differentiation, and that alterations in this cluster promote melanoma metastasis, perhaps by conferring stem cell properties to melanoma cells. To test these hypotheses, we will first determine the transcriptional and epigenetic regulation of the miR-183-96-182 cluster in physiological and pathological contexts, from human embryonic stem cell stage through melanocyte differentiation and in melanoma cells (Aim 1).
In Aim 2 we will test whether miR-183-96-182 and/or KLF4 confer stem-cell-like properties (e.g., self-renewal, multi-differentiation capacity) on melanoma cells through several cell-based assays.
In Aim 3, we will determine how modulation of this miRNA cluster and/or KLF4 influence the propensity of melanoma cells for metastasis in mice. Understanding the mechanisms that modulate miR-183-96-182 overexpression, which is clearly involved in metastasis, could provide a foothold for altering the aggressiveness of this very aggressive cancer, and perhaps provide a framework for similar studies in other recalcitrant cancer types.
We have found that the microRNA cluster miR-183-96-182 is frequently over-expressed in melanoma and contributes to metastasis, a process that is a key cause of cancer mortality yet is poorly understood. We seek to understand metastasis and its molecular relationship to developmental programs in melanoma. Our findings will provide a better understanding of melanoma aggressive behavior and potential targets for therapeutic intervention.
|Santamaría, Patricia G; Floristán, Alfredo; Fontanals-Cirera, Bárbara et al. (2018) Lysyl oxidase-like 3 is required for melanoma cell survival by maintaining genomic stability. Cell Death Differ 25:935-950|
|Díaz-Martínez, Marta; Benito-Jardón, Lucía; Alonso, Lola et al. (2018) miR-204-5p and miR-211-5p Contribute to BRAF Inhibitor Resistance in Melanoma. Cancer Res 78:1017-1030|
|Fontanals-Cirera, Barbara; Hasson, Dan; Vardabasso, Chiara et al. (2017) Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene. Mol Cell 68:731-744.e9|
|Segura, Miguel F; Jubierre, Luz; Li, SiDe et al. (2017) Krüppel-like factor 4 (KLF4) regulates the miR-183~96~182 cluster under physiologic and pathologic conditions. Oncotarget 8:26298-26311|
|Koetz-Ploch, Lisa; Hanniford, Douglas; Dolgalev, Igor et al. (2017) MicroRNA-125a promotes resistance to BRAF inhibitors through suppression of the intrinsic apoptotic pathway. Pigment Cell Melanoma Res 30:328-338|
|Martinez-Ruiz, Haydeliz; Illa-Bochaca, Irineu; Omene, Coral et al. (2016) A TGF?-miR-182-BRCA1 axis controls the mammary differentiation hierarchy. Sci Signal 9:ra118|
|Barbáchano, A; Fernández-Barral, A; Pereira, F et al. (2016) SPROUTY-2 represses the epithelial phenotype of colon carcinoma cells via upregulation of ZEB1 mediated by ETS1 and miR-200/miR-150. Oncogene 35:2991-3003|
|Silva, Ines P; Salhi, Amel; Giles, Keith M et al. (2016) Identification of a Novel Pathogenic Germline KDR Variant in Melanoma. Clin Cancer Res 22:2377-85|
|Vardabasso, Chiara; Gaspar-Maia, Alexandre; Hasson, Dan et al. (2015) Histone Variant H2A.Z.2 Mediates Proliferation and Drug Sensitivity of Malignant Melanoma. Mol Cell 59:75-88|
|Danielson, Laura S; Reavie, Linsey; Coussens, Marc et al. (2015) Limited miR-17-92 overexpression drives hematologic malignancies. Leuk Res 39:335-41|
Showing the most recent 10 out of 19 publications