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Cancer-initiating cells in human pancreatic cancer organoids are maintained by interactions with endothelial cells

Authors
 Choi, Jae-Il  ;  Jang, Sung Ill  ;  Hong, Jaehyun  ;  Kim, Chul Hoon  ;  Kwon, Soon Sung  ;  Park, Joon Seong  ;  Lim, Jong-Baeck 
Citation
 CANCER LETTERS, Vol.498 : 42-53, 2021-02 
Journal Title
 CANCER LETTERS 
ISSN
 0304-3835 
Issue Date
2021-02
Keywords
Human cancer organoid ; Cancer stem cells ; Vascular niche ; Tumor microenvironment ; Cancer plasticity
Abstract
Pancreatic ductal adenocarcinoma (PDAC) shows poor prognosis and high malignancy due to the presence of cancer-initiating cells (CICs) and characteristics of the tumor microenvironment (TME). Organoids are useful for studying PDAC, and establishing organoids is dependent on stem cell growth factors, including Wnt signaling. Herein, using a conventional organoid culture system, we demonstrated that CD44(+)CD24(+) and CD44(+) CD24(+)EpCAM(+) CICs were enriched >65% in a PDAC patient-derived organoid. CICs expressing CD44 formed lumen structures by gathering into circles. Additionally, organoid-derived CD44(-) cancer cells were capable of organoid re-formation and could be re-programed as CD44-expressing CICs in the organoid culture system. To mimic a TME absent artificial stem cell growth factors, a PDAC organoid with vascular niche was established. CICs in the PDAC tumor organoid were maintained by paracrine effects and direct interactions with endothelial cells. Interestingly, CD44(+) cells in PDAC tumor tissue were detected primarily in the vascular niche. Inhibiting both Wnt and Notch signaling in endothelial cells suppressed organoid formation and the maintenance of CD24(+)CD44(+) CICs. Collectively, our results suggest that PDAC patient-derived organoids maintain CICs by interacting with endothelial cells via Wnt and Notch pathways.
DOI
10.1016/j.canlet.2020.10.012
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Laboratory Medicine (진단검사의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kwon, Sun Sung(권순성)
Kim, Chul Hoon(김철훈) ORCID logo https://orcid.org/0000-0002-7360-429X
Park, Joon Seong(박준성) ORCID logo https://orcid.org/0000-0001-8048-9990
Lim, Jong Baeck(임종백) ORCID logo https://orcid.org/0000-0003-0419-0422
Jang, Sung Ill(장성일) ORCID logo https://orcid.org/0000-0003-4937-6167
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/181845
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