Abstract 3021: Plexin-B3 regulates cellular motility, invasiveness and metastasis in pancreatic cancer

Abstract

Abstract Cancer metastasis significantly worsens the survival of pancreatic cancer (PC) patients. Currently, semaphorins and their high-affinity receptors plexins are considered versatile regulators of cancer cell migration, angiogenesis, invasion and metastasis. Our group identified semaphorin-5A (SEMA5A) as a putative cell adhesion molecule involved in organ-specific homing of PC cells and playing a significant role in PC angiogenesis and metastasis. Thus, SEMA5A and its receptor plexin-B3 represents an attractive targetable axis in PC metastasis. However, for a better understanding of the SEMA5A-initiated downstream signaling events and regulation of cellular phenotypes, it is necessary to delineate the function of its receptor plexin-B3 in PC as well. Thus, understanding the pathologic expression and functional role of plexin-B3 is essential for characterization of SEMA5A/plexin-B3 axis in PC. In the present study, we analyzed plexin-B3 expression in PC disease progression model of PDX-Cre-Kras(G12D) (KC) mice and evaluated the functional role by utilizing plexin-B3 knockdown T3M-4 and CD18/HPAF cells. We observed a reduction of plexin-B3 expression with disease progression in KC mice model and also the poor survival of pancreatic adenocarcinoma stage II patients (n = 24) with lower plexin-B3 expression. Functionally, knockdown of plexin-B3 enhanced in vitro cellular migration and invasiveness of PC cells. Furthermore, plexin-B3 knockdown cells showed a significant increase in cellular size with impaired colony formation in three-dimensional culture. Cell proliferation analysis demonstrated that plexin-B3 knockdown cells showed lower proliferation in comparison with the control cells. We also observed higher metastasis with lower tumor burden in nude mice injected with CD18/HPAF-sh plexin-B3 cells than CD18/HPAF-control cells. Furthermore, the tumors formed by CD18/HPAF-plexin-B3 cells showed higher fibrosis, a higher number of vimentin-positive cells, and lower number of proliferation marker Ki-67-positive cells in comparison with the CD18/HPAF-control tumors. In addition, we observed similar phenotypic changes in PC cells with loss of SEMA5A-ligand of plexin-B3. In summary, our data demonstrate that impairment in SEMA5A/plexin-B3 axis enhances cellular motility and invasiveness of PC cells, thereby resulting in higher metastasis. Citation Format: Sugandha Saxena, Yuri Hayashi, Satyanarayana Rachagani, Surinder Kumar Batra, Rakesh Kumar Singh. Plexin-B3 regulates cellular motility, invasiveness and metastasis in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3021.