Stabilized epithelial phenotype of cancer cells in primary tumors leads to increased colonization of liver metastasis in pancreatic cancer.

Julienne L Carstens,Souptik Barua,Arvind Rao,Sujuan Yang,Kathleen M Mcandrews,Jared K Burks,Xiaofeng Zheng,Pedro Correa De Sampaio,Raghu Kalluri,Andrew D Rhim

doi:10.1016/j.celrep.2021.108990

Abstract

SUMMARYPancreatic 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.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is a treatment-resistant, deadly disease with a 5-year survival rate of 9% and metastatic disease emerging in nearly 98% of patients (Siegel et al, 2019; Hidalgo, 2010)
We further explored the impact of stabilized partial EMT (pEMT) states on PDAC metastasis via the use of multiple genetically engineered mouse models (GEMMs) that exhibit a stabilized epithelial phenotype through the deletion of epithelial-to-mesenchymal transition (EMT)-driving transcription factors
Single-cell RNA-seq of human PDAC reveals 51 different cancer cell phenotypes across the EMT continuum To examine the prevalence of different EMT states in human PDAC, we evaluated the single-cell RNA-seq dataset of >57,000 individual cells from 27 PDAC patient primary tumors (Peng et al, 2019)

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is a treatment-resistant, deadly disease with a 5-year survival rate of 9% and metastatic disease emerging in nearly 98% of patients (Siegel et al, 2019; Hidalgo, 2010). EMT is not a simple binary process, either epithelial or mesenchymal, but instead a plastic continuum of partial EMT (pEMT) states between the epithelial and mesenchymal poles (Jolly et al, 2018; Kalluri and Weinberg, 2009; Lovisa et al, 2015, 2016; Brabletz et al, 2018; Aiello et al, 2018; Williams et al, 2019; da Silva-Diz et al, 2018; Yang et al, 2020) Such pEMT cells have been suggested as being important in cancer metastasis and drug resistance (Yang et al, 2020). The role of EMT in therapy resistance has been validated by multiple studies, but evidence for its requirement for metastasis is still evolving (Brabletz et al, 2018; Dongre and Weinberg, 2019; Williams et al, 2019; Liu et al, 2014)

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Conclusion