Abstract A61: Dissecting the molecular basis of Ewing's sarcoma metastasis

Abstract

Abstract Ewing's sarcoma family of tumors is a group of poorly differentiated malignant pediatric cancers of bone and soft tissue. About 25% of patients present with clinically detectable metastases. Despite aggressive therapy, little improvement has been seen in patients with metastatic disease due to the lack of understanding of the molecular pathways that regulate its spread. There has been immunohistologic and gene expression profiling analyses indicating a striking similarity between Ewing's sarcoma and fetal and neuronal tissues. We hypothesize that a group of genes that regulate a specialized group of embryonic stem cells (neural crest cells) are reactivated to allow Ewing's sarcoma cells to metastasize. We examined primary human Ewing's sarcoma samples to detect the expression of one of those genes, the Twist1 transcription factor. Twenty Ewing's sarcoma samples were strongly positive for Ewing's sarcoma marker CD99, confirming the correct tumor type. Interestingly 88% (8/11) of metastatic Ewing's sarcoma patients had strong nuclear staining of Twist1 by immunohistochemistry (IHC). In contrast, only 17% (1/6) of non-metastatic tumor samples showed positive Twist1 signals, thus indicating that expression of Twist1 is tightly associated with metastasis in Ewing's sarcoma (P <0.05). Notably Twist1 positivity is also an independent prognostic marker for poor survival in this group of patients. 7 out of the 8 (88%) Twist1 positive patients died from disease versus only 2 out of 8 (25%) in the Twist1 negative patients (p < 0.05). In addition we explored PDGFRα as a possible target for therapy given that PDGFRα is a direct transcription target of Twist1. Indeed PDGFRα expression was significantly associated with Twist1 and also tightly linked to survival (P<0.05) in these patients. In summary, these results suggest that reactivation of the neural crest migration program through Twist1 plays a critical role in promoting metastasis in Ewing's sarcoma. Functional studies on the role of Twist1 and PDGFRα in Ewing's sarcoma metastasis are ongoing and may lead to targeted therapies against this unique developmental pathway to combat Ewing's sarcoma metastasis. Citation Format: Sun Choo, Jing Yang. Dissecting the molecular basis of Ewing's sarcoma metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A61.