Distinct Patterns of Ciliation in Divergent Classes of Melanocytic Lesions
Salma Dabiri, Elliott S Seeley, Jinah Kim. Stanford, Stanford, CA
Background: Primary cilia are ubiquitous sensory organelles that coordinate tissue development and adaptation. Defects in ciliogenesis are associated with the induction of pro-oncogenic signaling and primary cilia can enhance or repress the development of Hedgehog-dependent cancers; however, the role and fate of these organelles in malignancies such as melanoma, which are driven primarily by other signaling pathways, is unclear.
Design: Using a combination of melanocyte, primary cilium and basal body-specific antibodies in conjunction with confocal microscopy, we examined a total of 87 melanocytic lesions, including 22 common nevi, 16 primary cutaneous melanoma in situs, 16 primary cutaneous invasive melanomas, 8 primary cutaneous nodal metastases, 7 Spitz nevi, and 18 primary mucosal melanomas for the abundance of primary cilia.
Results: Nearly all melanocytes in common melanocytic nevi are ciliated whereas there is a near-complete loss of these organelles in primary cutaneous melanoma in situ, primary cutaneous invasive melanoma, and metastatic melanoma of cutaneous origin. In contrast, the frequency of ciliated melanocytes is reduced in Spitz nevi and variable in primary mucosal melanoma.
Conclusions: In cutaneous melanomas, which are driven by hyperactivation of the Ras-Raf-MAPK signaling axis in the vast majority of cases, the loss of the primary cilium occurs initially during the development of melanoma in situ and is sustained throughout subsequent disease progression. However, in mucosal melanomas, which feature genetics substantially divergent from those of cutaneous melanoma, ciliation is variable. The patterns of ciliation amongst malignant melanoma from distinct anatomic sites further supports the concept that each melanoma subtype may utilize a distinct repertoire of oncogenic signaling pathways and that the primary cilium may serve either tumor suppressive or pro-oncogenic functions, depending on the subtype of melanoma. Spitz nevi, which harbor unique genetic aberrations not observed in common nevi or cutaneous melanoma, retain cilia but at a reduced frequency when compared to common nevi. The pattern of ciliation observed among Spitz nevi would suggest that these nevi arise via mechanisms different than those of common nevi and cutaneous melanoma. Altogether, our findings parallel the reported genetic heterogeneity observed among these diverse lesions and suggest that the presence of the organelle may be an indication of particular driving mutations.
Wednesday, March 21, 2012 1:00 PM
Poster Session VI # 119, Wednesday Afternoon