Abstract 1699: Differential aggregation rates and therapeutic response of pancreatic cancer cell lines to sigma-2 receptor activation in 3D culture

Abstract

Abstract Pancreatic cancer is one of the most deadly forms of cancer, with overall 5-year survival rates under 20%. The only cure for this type of cancer is surgical, however this option is rarely available due in part to detection that is typically late in the progression of the disease. The aim of this study was to understand the differences in progression between L3.6, PANC-1, and M1A-PaCa-2 cells as representatives of varied levels of metastatic character through aggregation analysis in 3D cell culture. It is well established that 3D culture more closely mimics the in vivo condition, as the cells adhere to each other forming “microtumors” as opposed to being attached to a plastic substratum as is the case with standard 2D cell culture. We also examined the effectiveness of a novel target for chemotherapeutic intervention in these cell lines in 3D culture. The sigma-2 receptor is highly upregulated in rapidly proliferating cancer tissues as compared to non-cancerous tissue, and induces apoptosis when activated. We previously reported the ability of the sigma-2 receptor partial agonist CM572 (sigma-2 Ki = 14.7 nM) to induce apoptosis in PANC-1 pancreatic carcinoma cells in standard 2D culture (Nicholson et al., Proc. Amer. Assoc. Cancer Res. 74: #3237, 2014). Here, we measured the aggregation rate and sigma-2 agonist sensitivity of L3.6, a highly metastatic cell line, in comparison to M1A-PaCa-2 and PANC-1 cells, which are both significantly less aggressive. The sigma-2 receptor agonist siramesine (Ki = 0.12nM) was found to induce cell death in 3D tumor cell culture in all three pancreatic cancer cell lines. However, the potency was 30-50% of the potency observed in traditional 2D cultured cells. Interestingly, in 3D culture, L3.6 and PANC-1 cells both exhibited ∼45% of the maximal cell death that was achieved in 2D culture using the same dose of siramesine, and M1A-PaCa-2 cells exhibited ∼25% of the maximal 2D toxicity at this dose. Additionally, both siramesine and CM572 were able to slow aggregation of the pancreatic cancer cells. This data indicates that the sigma-2 receptor may provide a novel target for therapeutic intervention in pancreatic cancer, both for slowing progression of the disease and as a chemotherapeutic target. The data also indicate that cell-cell contact in 3D culture either modifies the sigma-2 receptor signaling process or that cells in 3D culture present more of a barrier for drug access to the tumor cells. Further studies are needed to examine these possibilities. Citation Format: Timothy Chou, Michaela Jacobs, Hilary Nicholson, Wayne D. Bowen. Differential aggregation rates and therapeutic response of pancreatic cancer cell lines to sigma-2 receptor activation in 3D culture. [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 1699. doi:10.1158/1538-7445.AM2015-1699