Stabilized epithelial phenotype of cancer cells in primary tumors leads to increased colonization of liver metastasis in pancreatic cancer
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
Affiliations
Julienne L. Carstens
Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Sujuan Yang
Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Pedro Correa de Sampaio
Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Xiaofeng Zheng
Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Souptik Barua
Department of Electrical and Computer Engineering, Rice University, Houston, TX 77030, USA
Kathleen M. McAndrews
Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Arvind Rao
Department of Computational Medicine and Bioinformatics, Biostatistics, Radiation Oncology, University of Michigan, Ann Arbor, MI 48105, USA
Jared K. Burks
Department of Leukemia, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Andrew D. Rhim
Department of Gastroenterology, Hepatology, and Nutrition, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
Raghu Kalluri
Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Department of Bioengineering, Rice University, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Corresponding author
Summary: Pancreatic ductal adenocarcinoma (PDAC) is therapeutically recalcitrant and metastatic. Partial epithelial to mesenchymal transition (EMT) is associated with metastasis; however, a causal connection needs further unraveling. Here, we use single-cell RNA sequencing and genetic mouse models to identify the functional roles of partial EMT and epithelial stabilization in PDAC growth and metastasis. A global EMT expression signature identifies ∼50 cancer cell clusters spanning the epithelial-mesenchymal continuum in both human and murine PDACs. The combined genetic suppression of Snail and Twist results in PDAC epithelial stabilization and increased liver metastasis. Genetic deletion of Zeb1 in PDAC cells also leads to liver metastasis associated with cancer cell epithelial stabilization. We demonstrate that epithelial stabilization leads to the enhanced collective migration of cancer cells and modulation of the immune microenvironment, which likely contribute to efficient liver colonization. Our study provides insights into the diverse mechanisms of metastasis in pancreatic cancer and potential therapeutic targets.
