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Cancer-Associated Fibroblasts Provide a Stromal Niche for Liver Cancer Organoids That Confers Trophic Effects and Therapy Resistance

BACKGROUND & AIMS: Cancer-associated fibroblasts (CAFs) play a key role in the cancer process, but the research progress is hampered by the paucity of preclinical models that are essential for mechanistic dissection of cancer cell–CAF interactions. Here, we aimed to establish 3-dimensional (3D)...

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Autores principales: Liu, Jiaye, Li, Pengfei, Wang, Ling, Li, Meng, Ge, Zhouhong, Noordam, Lisanne, Lieshout, Ruby, Verstegen, Monique M.A., Ma, Buyun, Su, Junhong, Yang, Qin, Zhang, Ruyi, Zhou, Guoying, Carrascosa, Lucia Campos, Sprengers, Dave, IJzermans, Jan N.M., Smits, Ron, Kwekkeboom, Jaap, van der Laan, Luc J.W., Peppelenbosch, Maikel P., Pan, Qiuwei, Cao, Wanlu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788239/
https://www.ncbi.nlm.nih.gov/pubmed/32932015
http://dx.doi.org/10.1016/j.jcmgh.2020.09.003
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author Liu, Jiaye
Li, Pengfei
Wang, Ling
Li, Meng
Ge, Zhouhong
Noordam, Lisanne
Lieshout, Ruby
Verstegen, Monique M.A.
Ma, Buyun
Su, Junhong
Yang, Qin
Zhang, Ruyi
Zhou, Guoying
Carrascosa, Lucia Campos
Sprengers, Dave
IJzermans, Jan N.M.
Smits, Ron
Kwekkeboom, Jaap
van der Laan, Luc J.W.
Peppelenbosch, Maikel P.
Pan, Qiuwei
Cao, Wanlu
author_facet Liu, Jiaye
Li, Pengfei
Wang, Ling
Li, Meng
Ge, Zhouhong
Noordam, Lisanne
Lieshout, Ruby
Verstegen, Monique M.A.
Ma, Buyun
Su, Junhong
Yang, Qin
Zhang, Ruyi
Zhou, Guoying
Carrascosa, Lucia Campos
Sprengers, Dave
IJzermans, Jan N.M.
Smits, Ron
Kwekkeboom, Jaap
van der Laan, Luc J.W.
Peppelenbosch, Maikel P.
Pan, Qiuwei
Cao, Wanlu
author_sort Liu, Jiaye
collection PubMed
description BACKGROUND & AIMS: Cancer-associated fibroblasts (CAFs) play a key role in the cancer process, but the research progress is hampered by the paucity of preclinical models that are essential for mechanistic dissection of cancer cell–CAF interactions. Here, we aimed to establish 3-dimensional (3D) organotypic co-cultures of primary liver tumor–derived organoids with CAFs, and to understand their interactions and the response to treatment. METHODS: Liver tumor organoids and CAFs were cultured from murine and human primary liver tumors. 3D co-culture models of tumor organoids with CAFs and Transwell culture systems were established in vitro. A xenograft model was used to investigate the cell–cell interactions in vivo. Gene expression analysis of CAF markers in our hepatocellular carcinoma cohort and an online liver cancer database indicated the clinical relevance of CAFs. RESULTS: To functionally investigate the interactions of liver cancer cells with CAFs, we successfully established murine and human 3D co-culture models of liver tumor organoids with CAFs. CAFs promoted tumor organoid growth in co-culture with direct cell–cell contact and in a Transwell system via paracrine signaling. Vice versa, cancer cells secrete paracrine factors regulating CAF physiology. Co-transplantation of CAFs with liver tumor organoids of mouse or human origin promoted tumor growth in xenograft models. Moreover, tumor organoids conferred resistance to clinically used anticancer drugs including sorafenib, regorafenib, and 5-fluorouracil in the presence of CAFs, or the conditioned medium of CAFs. CONCLUSIONS: We successfully established murine and human 3D co-culture models and have shown robust effects of CAFs in liver cancer nurturing and treatment resistance.
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spelling pubmed-77882392021-01-11 Cancer-Associated Fibroblasts Provide a Stromal Niche for Liver Cancer Organoids That Confers Trophic Effects and Therapy Resistance Liu, Jiaye Li, Pengfei Wang, Ling Li, Meng Ge, Zhouhong Noordam, Lisanne Lieshout, Ruby Verstegen, Monique M.A. Ma, Buyun Su, Junhong Yang, Qin Zhang, Ruyi Zhou, Guoying Carrascosa, Lucia Campos Sprengers, Dave IJzermans, Jan N.M. Smits, Ron Kwekkeboom, Jaap van der Laan, Luc J.W. Peppelenbosch, Maikel P. Pan, Qiuwei Cao, Wanlu Cell Mol Gastroenterol Hepatol Original Research BACKGROUND & AIMS: Cancer-associated fibroblasts (CAFs) play a key role in the cancer process, but the research progress is hampered by the paucity of preclinical models that are essential for mechanistic dissection of cancer cell–CAF interactions. Here, we aimed to establish 3-dimensional (3D) organotypic co-cultures of primary liver tumor–derived organoids with CAFs, and to understand their interactions and the response to treatment. METHODS: Liver tumor organoids and CAFs were cultured from murine and human primary liver tumors. 3D co-culture models of tumor organoids with CAFs and Transwell culture systems were established in vitro. A xenograft model was used to investigate the cell–cell interactions in vivo. Gene expression analysis of CAF markers in our hepatocellular carcinoma cohort and an online liver cancer database indicated the clinical relevance of CAFs. RESULTS: To functionally investigate the interactions of liver cancer cells with CAFs, we successfully established murine and human 3D co-culture models of liver tumor organoids with CAFs. CAFs promoted tumor organoid growth in co-culture with direct cell–cell contact and in a Transwell system via paracrine signaling. Vice versa, cancer cells secrete paracrine factors regulating CAF physiology. Co-transplantation of CAFs with liver tumor organoids of mouse or human origin promoted tumor growth in xenograft models. Moreover, tumor organoids conferred resistance to clinically used anticancer drugs including sorafenib, regorafenib, and 5-fluorouracil in the presence of CAFs, or the conditioned medium of CAFs. CONCLUSIONS: We successfully established murine and human 3D co-culture models and have shown robust effects of CAFs in liver cancer nurturing and treatment resistance. Elsevier 2020-09-12 /pmc/articles/PMC7788239/ /pubmed/32932015 http://dx.doi.org/10.1016/j.jcmgh.2020.09.003 Text en © 2020 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Original Research
Liu, Jiaye
Li, Pengfei
Wang, Ling
Li, Meng
Ge, Zhouhong
Noordam, Lisanne
Lieshout, Ruby
Verstegen, Monique M.A.
Ma, Buyun
Su, Junhong
Yang, Qin
Zhang, Ruyi
Zhou, Guoying
Carrascosa, Lucia Campos
Sprengers, Dave
IJzermans, Jan N.M.
Smits, Ron
Kwekkeboom, Jaap
van der Laan, Luc J.W.
Peppelenbosch, Maikel P.
Pan, Qiuwei
Cao, Wanlu
Cancer-Associated Fibroblasts Provide a Stromal Niche for Liver Cancer Organoids That Confers Trophic Effects and Therapy Resistance
title Cancer-Associated Fibroblasts Provide a Stromal Niche for Liver Cancer Organoids That Confers Trophic Effects and Therapy Resistance
title_full Cancer-Associated Fibroblasts Provide a Stromal Niche for Liver Cancer Organoids That Confers Trophic Effects and Therapy Resistance
title_fullStr Cancer-Associated Fibroblasts Provide a Stromal Niche for Liver Cancer Organoids That Confers Trophic Effects and Therapy Resistance
title_full_unstemmed Cancer-Associated Fibroblasts Provide a Stromal Niche for Liver Cancer Organoids That Confers Trophic Effects and Therapy Resistance
title_short Cancer-Associated Fibroblasts Provide a Stromal Niche for Liver Cancer Organoids That Confers Trophic Effects and Therapy Resistance
title_sort cancer-associated fibroblasts provide a stromal niche for liver cancer organoids that confers trophic effects and therapy resistance
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788239/
https://www.ncbi.nlm.nih.gov/pubmed/32932015
http://dx.doi.org/10.1016/j.jcmgh.2020.09.003
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