Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model
Abstract 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...
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Nature Portfolio
2021
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oai:doaj.org-article:4dd4de5030214100981257e70a7cbe462021-12-02T13:20:12ZAdipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model10.1038/s41598-021-84058-32045-2322https://doaj.org/article/4dd4de5030214100981257e70a7cbe462021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84058-3https://doaj.org/toc/2045-2322Abstract 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.Yoshihiro MiyazakiTatsuya OdaYuki InagakiHiroko KushigeYutaka SaitoNobuhito MoriYuzo TakayamaYutaro KumagaiToutai MitsuyamaYasuyuki S. KidaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021) |
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Medicine R Science Q Yoshihiro Miyazaki Tatsuya Oda Yuki Inagaki Hiroko Kushige Yutaka Saito Nobuhito Mori Yuzo Takayama Yutaro Kumagai Toutai Mitsuyama Yasuyuki S. Kida Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model |
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Abstract 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. |
format |
article |
author |
Yoshihiro Miyazaki Tatsuya Oda Yuki Inagaki Hiroko Kushige Yutaka Saito Nobuhito Mori Yuzo Takayama Yutaro Kumagai Toutai Mitsuyama Yasuyuki S. Kida |
author_facet |
Yoshihiro Miyazaki Tatsuya Oda Yuki Inagaki Hiroko Kushige Yutaka Saito Nobuhito Mori Yuzo Takayama Yutaro Kumagai Toutai Mitsuyama Yasuyuki S. Kida |
author_sort |
Yoshihiro Miyazaki |
title |
Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model |
title_short |
Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model |
title_full |
Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model |
title_fullStr |
Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model |
title_full_unstemmed |
Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model |
title_sort |
adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model |
publisher |
Nature Portfolio |
publishDate |
2021 |
url |
https://doaj.org/article/4dd4de5030214100981257e70a7cbe46 |
work_keys_str_mv |
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