Abstract 5797: Semaphorin 5A preserves epithelial phenotype in pancreatic cancer cells by regulating cross-talk between Wnt and TGF-β signaling

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 13_Supplement; p. 5797
• Main Authors: Saxena, Sugandha, Purohit, Abhilasha, Batra, Surinder K., Singh, Rakesh K.
• Format: Journal Article
• Language: English
• Published: 01.07.2017
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-5797

Abstract Pancreatic cancer (PC) is one of the deadliest forms of cancers. In spite of recent advances, minimal progress has been made in our understanding of PC progression, metastasis, and treatment of PC patients with advanced disease. Striking similarity between the process of cancer metastasis and guidance of neuronal cells to their target sites has generated interest in pharmacologically targeting guidance cue molecules for treatment of metastasis. Among the guidance cue family members, Semaphorin5A (SEMA5A), was found to be involved in organ-specific homing during PC metastasis. With an interest to delineate the function of SEMA5A in PC, we generated SEMA5A knockdown in metastatic PC cell lines. Knock down of SEMA5A expression resulted in loss of cellular differentiation and epithelial phenotype with higher motility as compared to vector control cells. This observation is in accordance with our previous finding that SEMA5A expression was higher in well-differentiated tumors in comparison with undifferentiated pancreatic tumors. Loss of SEMA5A increased TGF-β2 production, decreased expression of E-cadherin, and nuclear translocation of β-catenin. Furthermore, we observed higher Wnt activity and increased expression of the transcription factor SNAIL in SEMA5A knockdown cells in comparison with vector control cells. Higher Wnt signaling along with increased TGF-β2 production explains the loss of differentiation and epithelial markers. Moreover, we observed that non canonical TGF-β2/AKT mediated inhibition of GSK3-β is responsible for increased stability of β-catenin and SNAIL, thereby activating Wnt signaling in SEMA5A knockdown cells. Our observations demonstrate that SEMA5A has a potential role in maintaining the epithelial phenotype in PC cells by keeping cross-talk between Wnt and TGF-β signaling under check. Citation Format: Sugandha Saxena, Abhilasha Purohit, Surinder K. Batra, Rakesh K. Singh. Semaphorin 5A preserves epithelial phenotype in pancreatic cancer cells by regulating cross-talk between Wnt and TGF-β signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5797. doi:10.1158/1538-7445.AM2017-5797