Abstract 5626: FKBP51 is a crucial modulator of melanoma plasticity and promising molecular target for preventing melanoma metastasis

Abstract

Abstract FKBP51, a protein with a relevant role in developmental stages in mammals and other organisms, is highly expressed in melanoma and correlates with tumor aggressiveness and resistance to therapy. We found that FKBP51 positively regulates melanoma cancer stem cell (CSC) phenotype at the transcriptional level. We also found that melanoma CSCs are endowed with epithelial to mesenchimal transition (EMT) traits. The immunochemistry study of 10 primitive cutaneous and 20 brain melanoma metastases showed that melanocytic cells capable of extravasation and subverting the architecture of metastatic tissue display intense FKBP51 nuclear signal and cytoplasmic positivity for the CSC marker nestin. These findings support the conclusion that the genetic programs of cancer stemness and invasiveness overlap in melanoma, and that FKBP51 plays a pivotal role in sustaining such a program. To confirm the role of FKBP51 in melanoma invasion, we utilized an experimental metastasis model. Animal studies were performed in accordance with NIH recommendations and the approval of the local institutional animal research committee. Injecting SAN melanoma cells into the tail vein of IL2γ-NOD-SCID mice produced prominent multifocal lesions in lungs and liver. We systemically administered two separate doses of FKBP51 siRNA to mice after the injection of melanoma cells. Organ colonization was evaluated both in live animals and post mortem. Qualitative PET/CT image analysis demonstrated low FDG uptake limited to small areas in lungs and liver. By contrast, untreated mice had diffuse metastatic liver and lung lesions and high FDG uptake in the same organs. Quantitative analysis performed on PET/CT images revealed that mean standardized uptake values (SUV) in treated mice were significantly lower than in untreated mice, both for lungs and liver. High Frequency Ultrasound examination revealed few or no liver metastases in treated mice versus untreated mice. Post-mortem organ examination showed a dramatic difference between the morphologically preserved organs dissected from treated mice, and severely compromised organs from untreated mice. The histological examination confirmed these findings. Most interestingly, invading cells co-expressed FKBP51 and nestin. Our study suggests a prominent role for FKBP51 in the pathogenesis of metastatic melanoma; we envision that targeting this protein for melanoma metastasis prevention may produce a successful outcome. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5626. doi:1538-7445.AM2012-5626