Hypoxia at 3D organoid establishment selects essential subclones within heterogenous pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is especially hypoxic and composed of heterogeneous cell populations containing hypoxia-adapted cells. Hypoxia as a microenvironment of PDAC is known to cause epithelial-mesenchymal transition (EMT) and resistance to therapy. Therefore, cells adapted to hypoxi...

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Vydáno v:Frontiers in cell and developmental biology Ročník 12; s. 1327772
Hlavní autoři: Kumano, Koichiro, Nakahashi, Hiromitsu, Louphrasitthiphol, Pakavarin, Kuroda, Yukihito, Miyazaki, Yoshihiro, Shimomura, Osamu, Hashimoto, Shinji, Akashi, Yoshimasa, Mathis, Bryan J., Kim, Jaejeong, Owada, Yohei, Goding, Colin R., Oda, Tatsuya
Médium: Journal Article
Jazyk:angličtina
Vydáno: Switzerland Frontiers Media SA 01.02.2024
Frontiers Media S.A
Témata:
3D organoid
Adenocarcinoma
Cell and Developmental Biology
Cell culture
Cell growth
Chemotherapy
Gene expression
Hypoxia
Microenvironments
Organoids
Pancreatic cancer
selection bias
Transcriptomes
tumor heterogeneity
Tumors
selection bias
hypoxia
pancreatic cancer
3D organoid
tumor heterogeneity
ISSN:2296-634X, 2296-634X
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Shrnutí:Pancreatic ductal adenocarcinoma (PDAC) is especially hypoxic and composed of heterogeneous cell populations containing hypoxia-adapted cells. Hypoxia as a microenvironment of PDAC is known to cause epithelial-mesenchymal transition (EMT) and resistance to therapy. Therefore, cells adapted to hypoxia possess malignant traits that should be targeted for therapy. However, current 3D organoid culture systems are usually cultured under normoxia, losing hypoxia-adapted cells due to selectivity bias at the time of organoid establishment. To overcome any potential selection bias, we focused on oxygen concentration during the establishment of 3D organoids. We subjected identical PDAC surgical samples to normoxia (O2 20%) or hypoxia (O2 1%), yielding glandular and solid organoid morphology, respectively. Pancreatic cancer organoids established under hypoxia displayed higher expression of EMT-related proteins, a Moffitt basal-like subtype transcriptome, and higher 5-FU resistance in contrast to organoids established under normoxia. We suggest that hypoxia during organoid establishment efficiently selects for hypoxia-adapted cells possibly responsible for PDAC malignant traits, facilitating a fundamental source for elucidating and developing new treatment strategies against PDAC.
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Edited by: Nikhil Baban Ghate, University of Southern California, United States
Yue J. Wang, Florida State University, United States
These authors have contributed equally to this work and share first authorship
Reviewed by: Hyomin Cho, Massachusetts General Hospital and Harvard Medical School, United States
ISSN:2296-634X
2296-634X
DOI:10.3389/fcell.2024.1327772