Abstract PO-059: Epithelial/mesenchymal identity dictates pancreatic cancer cell metastasis

Abstract

Abstract Metastatic pancreatic adenocarcinoma (PDAC) is the dominant clinical presentation and highly treatment-resistant. However, not all metastasis is equal with metastatic disease in the lung having improved outcomes over the liver. These clinical differences suggest a therapeutic opportunity and urge analysis of the molecular underpinnings of PDAC metastasis. The acquisition of mesenchymal features by epithelial cancer cells is commonly associated with solid tumor metastasis and has been linked to the pancreatic cancer basal subtype and its association with treatment resistance and poorer outcomes, but its impact on pancreatic cancer metastasis needs further understanding. We explored the impact on metastasis of stabilized epithelial, partial-mesenchymal and mesenchymal cancer cells by generating several genetic mouse models based on the lineage-traced KPC mouse model (KrasLSL-G12D;p53R172H; or p53LSL; PDX1-Cre;EYFPLSL). Using single-cell RNA-sequencing we confirmed the KPC mouse model recapitulates the spectrum of epithelial-mesenchymal phenotypes observed in patients and can be genetically engineered to stabilize specific phenotypes. The stabilization of epithelial phenotypes through the homozygous loss of the mesenchymal-driving transcription factors Snail and Twist (Snai1F/F;Twist1F/F) had no impact on primary tumor progression but increased liver colonization. This increase in liver colonization was supported by a second epithelial-stabilized mouse model based on the loss of Zeb1 (Zeb1F/F). The stabilization of mesenchymal features through the heterozygous or homozygous loss of the epithelial adherin junction E-cadherin (Cdh1F/+ or Cdh1F/F) promoted lung metastasis. Interestingly, epithelial plasticity was still required for efficient lung colonization, but not rare liver metastasis. Additionally, mesenchymal gene expression correlated with an improved patient survival as well as metastatic localization, supporting the clinical observations of improved survival in lung metastasis. Using gene expression analysis of sorted bulk cancer cells and single-cells, migration assays, and multiplexed-immunohistochemistry, we observed that the epithelial/mesenchymal status of the cancer cells dictated different mechanisms for motility and interaction with the immune system. Mesenchymal cancer cells migrate as single-cells and attract fewer T-cells where epithelial cancer cells migrate collectively and have increased immune regulation gene expression. These data suggest the epithelial/mesenchymal status of cancers cells dictate the where and how of metastatic disease and could inform therapeutic interventions. Citation Format: Julienne L. Carstens, Sujuan Yang, Pedro Correa de Sampaio, Xiaofeng Zheng, Souptik Barua, Kathleen M. McAndrews, Arvind Rao, Jared K. Burks, Andrew D. Rhim, Raghu Kalluri. Epithelial/mesenchymal identity dictates pancreatic cancer cell metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-059.