Oncotarget

Research Papers: Pathology:

Anchorage-dependent multicellular aggregate formation induces a quiescent stem-like intractable phenotype in pancreatic cancer cells

Yukiko Miyatake _, Yusuke Ohta, Shunji Ikeshita and Masanori Kasahara

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Oncotarget. 2018; 9:29845-29856. https://doi.org/10.18632/oncotarget.25732

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Abstract

Yukiko Miyatake1,*, Yusuke Ohta1,*, Shunji Ikeshita1 and Masanori Kasahara1

1Department of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, 060-8638, Japan

*These authors contributed equally to this work

Correspondence to:

Yukiko Miyatake, email: yukimiya@med.hokudai.ac.jp

Keywords: pancreatic cancer; collective cell behavior; Ad-MCA; coculture; HEK293T; Pathology

Received: May 22, 2018     Accepted: June 24, 2018     Published: July 06, 2018

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal refractory cancers. Aggressive features in PDAC cells have been well studied, but those exhibited by a population of PDAC cells are largely unknown. We show here that coculture with epithelial-like feeder cells confers more malignant phenotypes upon PDAC cells forming anchorage-dependent multicellular aggregates (Ad-MCAs, a behavior of collective cells), in vitro. When CD44v3-10high/CD44slow PDAC cell lines, which exhibited an epithelial phenotype before the onset of epithelial–mesenchymal transition (EMT), were cocultured with a monolayer of HEK293T cells overnight, they formed Ad-MCAs on the feeder layer and acquired gemcitabine resistance. CD44v8-10 expression was dramatically increased and Ki-67 staining decreased, suggesting that PDAC cells forming Ad-MCAs acquired cancer stem cell (CSC)-like intractable properties. We found that highly downregulated genes in PDAC cells cocultured with HEK293T cells were significantly upregulated in malignant lesions from pancreatic cancer patients. Our work implies that PDAC cells forming Ad-MCAs partially return to a normal tissue gene profile before the onset of EMT. The collective cell behavior like Ad-MCA formation by PDAC cells may mimic critical events that occur in cancer cells at the very early phase of metastatic colonization.


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