Faculty Bibliography

We examined the microRNA signature that distinguishes the most common melanoma histological subtypes, superficial spreading melanoma (SSM) and nodular melanoma (NM). We also investigated the mechanisms underlying the differential expression of histology-specific microRNAs. MicroRNA array performed on a training cohort of 82 primary melanoma tumors (26 SSM, 56 NM), and nine congenital nevi (CN) revealed 134 microRNAs differentially expressed between SSM and NM (P<0.05). Out of 134 microRNAs, 126 remained significant after controlling for thickness and 31 were expressed at a lower level in SSM compared with both NM and CN. For seven microRNAs (let-7g, miR-15a, miR-16, miR-138, miR-181a, miR-191, and miR-933), the downregulation was associated with selective genomic loss in SSM cell lines and primary tumors, but not in NM cell lines and primary tumors. The lower expression level of six out of seven microRNAs in SSM compared with NM was confirmed by real-time PCR on a subset of cases in the training cohort and validated in an independent cohort of 97 melanoma cases (38 SSM, 59 NM). Our data support a molecular classification in which SSM and NM are two molecularly distinct phenotypes. Therapeutic strategies that take into account subtype-specific alterations might improve the outcome of melanoma patients.

Sarcoidosis is a common systemic, noncaseating granulomatous disease of unknown etiology. The development of sarcoidosis has been associated with a number of environmental factors and genes. Cutaneous sarcoidosis, the "great imitator," can baffle clinicians because of its diverse manifestations and its ability to resemble both common and rare cutaneous diseases. Depending on the type, location, and distribution of the lesions, treatment can prevent functional impairment, symptomatic distress, scarring, and disfigurement. Numerous therapeutic options are available for the treatment of cutaneous sarcoidosis, but there are few well designed trials to guide practitioners on evidence-based, best practice management. In part I, we review the current knowledge and advances in the epidemiology, etiology, pathogenesis, and genetics of sarcoidosis, discuss the heterogeneous manifestations of cutaneous sarcoidosis, and provide a guide for treatment of cutaneous sarcoidosis.

Sarcoidosis is a multisystemic, granulomatous disease with protean manifestations and variable prognosis. Because the skin can be the only organ in which the disease is recognized, dermatologists may be responsible for the care of sarcoidosis patients. Therefore, dermatologists should be cognizant of the disease's extracutaneous manifestations to assure appropriate evaluation and treatment. Part II of this review describes the diagnostic approach and management of the extracutaneous manifestations of sarcoidosis.

Malignant melanoma is fatal in its metastatic stage. It is therefore essential to unravel the molecular mechanisms that govern disease progression to metastasis. MicroRNAs (miRs) are endogenous non-coding RNAs involved in tumourigenesis. Using a melanoma progression model, we identified a novel pathway controlled by miR-214 that coordinates metastatic capability. Pathway components include TFAP2C, homologue of a well-established melanoma tumour suppressor, the adhesion receptor ITGA3 and multiple surface molecules. Modulation of miR-214 influences in vitro tumour cell movement and survival to anoikis as well as extravasation from blood vessels and lung metastasis formation in vivo. Considering that miR-214 is known to be highly expressed in human melanomas, our data suggest a critical role for this miRNA in disease progression and the establishment of distant metastases.

Several reports have demonstrated a role for aberrant NOTCH signaling in melanoma genesis and progression, prompting us to explore if targeting this pathway is a valid therapeutic approach against melanoma. We targeted NOTCH signaling using RO4929097, a novel inhibitor of gamma secretase, which is a key component of the enzymatic complex that cleaves and activates NOTCH. The effects of RO4929097 on the oncogenic and stem cell properties of a panel of melanoma cell lines were tested both in vitro and in vivo, using xenograft models. In human primary melanoma cell lines, RO4929097 decreased the levels of NOTCH transcriptional target HES1. This was accompanied by reduced proliferation and impaired ability to form colonies in soft agar and to organize in tridimensional spheres. Moreover, RO4929097 affected the growth of human primary melanoma xenograft in NOD/SCID/IL2gammaR-/- mice and inhibited subsequent tumor formation in a serial xenotransplantation model, suggesting that inhibition of NOTCH signaling suppresses the tumor initiating potential of melanoma cells. In addition, RO4929097 decreased tumor volume and blocked the invasive growth pattern of metastatic melanoma cell lines in vivo. Finally, increased gene expression of NOTCH signaling components correlated with shorter post recurrence survival in metastatic melanoma cases. Our data support NOTCH inhibition as a promising therapeutic strategy against melanoma

A 22-year-old man presented with a 9-year history of multiple blue nodules on the medial aspect of his right arm. A biopsy specimen showed a cystic space with a cuboidal cellular lining that stained positive for alpha-smooth-muscle actin; these findings were consistent with multiple glomangiomas. We review the clinical and histopathologic characteristics of this rare entity