Abstract 2264: Dual effects of podoplanin on the regulation of cancer cell gene expression and platelet CLEC-2 signaling during cancer metastasis

Abstract

Abstract Podoplanin (PDPN) is frequently up-regulated in squamous cell carcinoma and is a marker for poor prognosis. PDPN facilitates cancer metastasis and tumor cell-induced platelet aggregation (TCIPA) by modulating cancer cell cytoskeleton reorganization and platelet C-type lectin-like receptor 2 (CLEC-2) activation. In this study, the effects of PDPN on the regulation of cancer cell gene expression and platelet CLEC-2 signaling are investigated. Using xenograft injection of the C6 glioma cells into nude mice as a metastatic model, the cells that colonized at lung tissue were isolated to establish a subline C6-Lung that was found to express high levels of PDPN. Knockdown of PDPN expression in C6-Lung resulted in the abrogation of TCIPA, indicating that PDPN plays a key role in platelet activation and TCIPA. Microarray analyses revealed differential gene expression signatures between low and high PDPN-expressed cells. Several genes were up-regulated (Sncg, Timp1, Mmp3 and Pla1a) and down-regulated (Calcb, Filip1, Agrn and Itga4) significantly in high PDPN-expressed C6-Lung cells. On the other hand, distinct platelet protein tyrosine phosphorylation profiles were revealed when platelets were treated with different CLEC-2 agonists including PDPN, aggretin and fucoidan. In addition to the activation of common CLEC-2 signaling proteins such as Src family kinase, Syk, and phospholipase Cγ2, Akt1/PDK1 and PKCμ were identified as the two novel signaling pathways activated by PDPN, indicating the presence of SFK-independent pathway downstream of CLEC-2. Our data together provide a definitive evidence for the presence of a unique network for PDPN-regulated cancer cell gene expression and platelet CLEC-2 signaling that shed a new insight for the functional roles of PDPN in cancer metastasis. Citation Format: Ching-Ping Tseng, Yao-Wen Chang, Pei-Wen Hsieh, Ju-Chien Cheng. Dual effects of podoplanin on the regulation of cancer cell gene expression and platelet CLEC-2 signaling during cancer metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2264. doi:10.1158/1538-7445.AM2015-2264