Abstract 195: The transmembrane mucin MUC1 modulates MAPK signaling dynamics in pancreatic cancer cells

Abstract The transmembrane mucin MUC1 plays several roles in the progression of pancreatic ductal adenocarcinoma (PDAC) and is associated with aggressive disease. One function of MUC1 is the regulation of intracellular signal transduction through association with transmembrane receptors like EGFR and Src. While multiple studies have shown that MUC1 can potentiate signaling mitogen activated protein kinases, such as ERK, it’s unclear how dynamic this process is in PDAC. Previous studies examining ERK signaling have shown that dynamics can play a major role in the overall response to cells to growth factor signaling. To examine the influence of MUC1 on dynamic signal transduction we established cell lines expressing fluorescent biosensors of mitogen activated protein kinase activity (ERK, JNK, and p38) using cell lines derived from either wildtype KPC tumors or MUC1 knockout tumors. Morphologically, MUC1 expressing KPC cells appeared more mesenchymal consistent with MUC1’s roles in mediating migration and invasion of tumor cells. By comparison, MUC1 knockout cells readily formed monolayers with epithelial morphology. Using time-lapse fluorescence microscopy, we examined whether these cells also exhibited differences in MAPK signaling over time and in response to EGF stimulation. At baseline, KPC wildtype cells showed sustained ERK activation consistent with constitutive activation via K-Ras G12D. In comparison, MUC1 KO cells while still exhibiting high levels of ERK activity would also undergo periodic pulses of on and off states suggesting that MUC1 contributes to sustained ERK activation in tumor cells. EGF stimulation was capable of inducing ERK activation in both KPC wildtype and MUC1 KO cells, but as before KPC wildtype cells exhibited sustained activation while MUC1 KO cells pulsed. Given the high constitutive ERK activity in KPC wildtype cells we hypothesized these cells may be more reliant on ERK activation to survive. Interestingly, while treatment with 25 nM trametinib had a stronger inhibitory effect on MUC1 knockout cells, viability assays suggest that MEK inhibition reduces KPC wildtype growth more strongly than in MUC1 KO cells. These findings suggest that the sustained ERK signaling promoted by MUC1 expression may make tumor cells more reliant on ERK signaling and more prone to MEK inhibition. Citation Format: Seth Thesing, Ryan Lee Hanson. The transmembrane mucin MUC1 modulates MAPK signaling dynamics in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 195.