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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA155234-02S1
Application #
8761356
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mietz, Judy
Project Start
2013-11-29
Project End
2015-11-28
Budget Start
2013-11-29
Budget End
2015-11-28
Support Year
2
Fiscal Year
2014
Total Cost
$162,573
Indirect Cost
$66,660
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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
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
Santamaría, Patricia G; Floristán, Alfredo; Fontanals-Cirera, Bárbara et al. (2017) Lysyl oxidase-like 3 is required for melanoma cell survival by maintaining genomic stability. Cell Death Differ :
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
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
Hanniford, Doug; Segura, Miguel F; Zhong, Judy et al. (2015) Identification of metastasis-suppressive microRNAs in primary melanoma. J Natl Cancer Inst 107:
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
Kourtis, Nikos; Moubarak, Rana S; Aranda-Orgilles, Beatriz et al. (2015) FBXW7 modulates cellular stress response and metastatic potential through ?HSF1 post-translational modification. Nat Cell Biol 17:322-332
Hanniford, Doug; Zhong, Judy; Koetz, Lisa et al. (2015) A miRNA-Based Signature Detected in Primary Melanoma Tissue Predicts Development of Brain Metastasis. Clin Cancer Res 21:4903-12

Showing the most recent 10 out of 13 publications