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Abstract 167: Semaphorin3D signaling in the invasion and metastasis of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA) is a devastating disease, with the lowest stage-combined 5-year survival rate of any cancer type at 8%. One major attribute for this poor prognosis is the lack of effective treatments in preventing and controlling metastasis. Previously, our lab has identified the secreted protein Semaphorin3D (Sema3D) to be involved in the invasion and metastasis of PDA. Sema3D is part of the axon guidance gene family, recently been reported to be the most frequently altered gene family in PDA. We have previously found Sema3D interacts with its co-receptors PlexinD1 and Neuropilin-1 to cause increased invasion and metastatic capabilities in PDA cells. We found expression of Sema3D and PlexinD1 increases progressively during PDA development. In addition, tumoral knockdown of Sema3D prolongs survival and reduces metastasis of PDA-bearing mice. Also, Sema3D abundance was found to be significantly associated with human metastatic disease formation. However, the molecular signaling of Sema3D in aiding increased PDA cell invasion and metastasis is unknown. In the present study, we found treatment of mutant KrasG12D PDA, KPC cells, with Sema3D increases the activation of ADP-ribosylation factor 6 (Arf6). Interestingly, mutant KrasG12D has recently been reported to signal with Arf6 causing increased glycolytic metabolic changes. We found treating KPC cells with Sema3D increased glycolytic gene expression and increased tumor cell lactic acid secretion. Blockage of PlexinD1, the Sema3D receptor, with neutralizing antibodies inhibits this increase in glycolytic gene expression. Additionally, Panc02 PDA cells, not expressing mutant Kras, intriguingly do not show increased Arf6 activation after Sema3D treatment, suggesting Sema3D signaling could provide a selective role in mutant Kras expressing cells. Also, we investigated the role of Sema3D-induced increased acidity on tumor associated macrophage polarization. Bone-marrow derived macrophages were polarized to an M1, anti-tumor, or M2, pro-tumor phenotype and co-cultured with KPC cells treated with Sema3D or control protein. Macrophages isolated from the co-culture treated with Sema3D had decreased expression of anti-tumor M1 and increased expression of pro-tumoral M2 polarization markers compared to control. Futhermore, to study Sema3D expression in PDA in vivo, we crossed conditional Sema3D knockout mice to KRASG12D TP53R172H PDX-1-CRE+/+ (KPC) mice to create the KRASG12D TP53R172H Sema3D-/- PDX-1-CRE+/+ KPCS mouse model. Current studies are using the KPCS model to evaluate the role of Sema3D in PDA tumor development and metastasis, as well as, examine changes in tumor associated macrophage polarization. Taken together, this study provides enhanced mechanistic understanding of the role of Sema3D in aiding tumor progression and metastasis and, provides support for targeting the axon guidance pathway for PDA metastasis. Citation Format: Noelle R. Jurcak, Stephen Muth, Kenji Fujiwara, Agnieszka Rucki, Kelly Foley, Adrian Murphy, Elizabeth M. Jaffee, Lei Zheng. Semaphorin3D signaling in the invasion and metastasis of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 167.