Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model

Cancer-associated fibroblasts (CAFs) are the key components of the densely proliferated stroma in pancreatic ductal adenocarcinoma (PDAC) and contribute to tumor progression and drug resistance. CAFs comprise heterogeneous subpopulations playing unique and vital roles. However, the commonly used mou...

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Bibliographic Details
Published in:Scientific reports 2021-02, Vol.11 (1), p.4690-4690, Article 4690
Main Authors: Miyazaki, Yoshihiro, Oda, Tatsuya, Inagaki, Yuki, Kushige, Hiroko, Saito, Yutaka, Mori, Nobuhito, Takayama, Yuzo, Kumagai, Yutaro, Mitsuyama, Toutai, Kida, Yasuyuki S.
Format: Article
Language:English
Subjects:
631/532/2074
631/67/1504
631/67/327
631/67/70
692/4028/67/1504
692/4028/67/327
692/4028/67/70
692/699/1503/1712
692/699/1503/1712/1713
Adenocarcinoma
Adipose Tissue - cytology
Animal models
Animals
Cancer
Carcinoma, Pancreatic Ductal - pathology
Cell Differentiation
Chemoresistance
Drug resistance
Fibroblasts
Fibroblasts - cytology
Heterografts
Humanities and Social Sciences
Humans
Mesenchymal stem cells
Mesenchymal Stem Cells - cytology
Mice
multidisciplinary
Pancreatic cancer
Pancreatic Neoplasms
Pancreatic Neoplasms - pathology
Ribonucleic acid
RNA
Science
Science (multidisciplinary)
Stem cell transplantation
Stem cells
Stroma
Stromal Cells - cytology
Subpopulations
Tumor microenvironment
Tumors
Xenografts
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Summary:Cancer-associated fibroblasts (CAFs) are the key components of the densely proliferated stroma in pancreatic ductal adenocarcinoma (PDAC) and contribute to tumor progression and drug resistance. CAFs comprise heterogeneous subpopulations playing unique and vital roles. However, the commonly used mouse models have not been able to fully reproduce the histological and functional characteristics of clinical human CAF. Here, we generated a human cell-derived stroma-rich CDX (Sr-CDX) model, to reproduce the clinical tumor microenvironment. By co-transplanting human adipose-derived mesenchymal stem cells (AD-MSCs) and a human PDAC cell line (Capan-1) into mice, the Sr-CDX model recapitulated the characteristics of clinical pancreatic cancer, such as accelerated tumor growth, abundant stromal proliferation, chemoresistance, and dense stroma formed from the heterogeneous CAFs. Global RNA sequencing, single-cell based RNA sequencing, and histological analysis of CAFs in the Sr-CDX model revealed that the CAFs of the Sr-CDX mice were derived from the transplanted AD-MSCs and composed of heterogeneous subpopulations of CAF, including known and unknown subtypes. These lines of evidences suggest that our new tumor-bearing mouse model has the potential to address an open question in CAF research, that is the mechanism of CAF differentiation.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-021-84058-3