Abstract 2884: Wnt11 dictates the patterns and latency of pulmonary micrometastatic disease in pancreatic cancer

Abstract

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a systemic disease characterized by early metastasis involving numerous pro-metastatic pathways. However, dominant drivers of early PDAC cell dissemination and metastasis remain poorly defined. The non-canonical Wnt-PCP pathway has been shown to promote cancer cell motility predominantly through Wnt ligand-mediated activation of frizzled receptors that result in cytoskeleton rearrangements. As one of these Wnt ligands, Wnt11, has been previously implicated in metastasis, we tested if Wnt11 significantly affects PDAC metastasis in vivo. Methods: LSL-KrasG12D/+, p53wmR172H/+, and p48-Cre alleles were crossed with and without a conditional Wnt11fl allele to generate cohorts of Wnt11 wildtype and knockout mice in the well-established KPC PDAC mouse model (KPwmC, n = 22; KPwmC-Wnt11fl/fl, n = 37). Both cohorts included mice with a conditional LSL-ROSA26-tdTomato reporter to identify and enumerate distant metastases. Mice were sacrificed when euthanasia criteria were met, and metastases were visualized via full organ fluorescence microscopy to identify tdTomato(+) signals. Liver and lung metastases were enumerated and measured through automated color range selection and manual counting. Metastases were classified by diameter as micrometastases (<100 uM), intermediate metastases (100-499 uM), or macrometastases (≥500 uM). Results: Primary pancreatic tumors from KPwmC and KPwmC-Wnt11fl/fl mice were similar in histologic appearance without gross alterations in peritumoral stroma. There were no differences in median overall survival between KPwmC and KPwmC-Wnt11fl/fl mice (185 vs. 193 days, p = 0.92). Pulmonary micrometastatic disease in mice <170 days at euthanasia was significantly lower in KPwmC-Wnt11fl/fl mice relative to KPwmC mice (mean number of metastases 88.8 vs. 1780, respectively; p = 0.009). Moreover, while pulmonary metastases in KPwmC mice were diffuse and miliary, the lungs of KPwmC-Wnt11fl/fl mice contained only scant, scattered metastases. No significant differences were observed in the mean number of intermediate-sized (0.5 vs. 27.4, p = 0.17) or macrometastases (0.0 vs 1.6, p = 0.13). Differences in metastatic tumor size or burden were not observed in liver metastases between each cohort. Conclusions: Wnt11 affects the pattern and latency of early metastasis to the lung but does not affect any stage of hepatic metastasis. The role of Wnt11 in PDAC metastasis is context dependent and may be related to factors inherent in the pre-metastatic niche. Citation Format: Eileen C. Donovan, Bingbing Dai, Jenying Deng, Christian M. Siangco, Xinqun Li, Erika Y. Faraoni, Sylvia M. Evans, Michael P. Kim. Wnt11 dictates the patterns and latency of pulmonary micrometastatic disease in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2884.