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Effects of hyperinsulinemia on pancreatic cancer development and the immune microenvironment revealed through single-cell transcriptomics
BACKGROUND: Hyperinsulinemia is independently associated with increased risk and mortality of pancreatic cancer. We recently reported that genetically reduced insulin production resulted in ~ 50% suppression of pancreatic intraepithelial neoplasia (PanIN) precancerous lesions in mice. However, only...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8862319/ https://www.ncbi.nlm.nih.gov/pubmed/35189981 http://dx.doi.org/10.1186/s40170-022-00282-z |
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author | Zhang, Anni M. Y. Chu, Ken H. Daly, Brian F. Ruiter, Titine Dou, Yan Yang, Jenny C. C. de Winter, Twan J. J. Chhuor, Justin Wang, Su Flibotte, Stephane Zhao, Yiwei Bernie Hu, Xiaoke Li, Hong Rideout, Elizabeth J. Schaeffer, David F. Johnson, James D. Kopp, Janel L. |
author_facet | Zhang, Anni M. Y. Chu, Ken H. Daly, Brian F. Ruiter, Titine Dou, Yan Yang, Jenny C. C. de Winter, Twan J. J. Chhuor, Justin Wang, Su Flibotte, Stephane Zhao, Yiwei Bernie Hu, Xiaoke Li, Hong Rideout, Elizabeth J. Schaeffer, David F. Johnson, James D. Kopp, Janel L. |
author_sort | Zhang, Anni M. Y. |
collection | PubMed |
description | BACKGROUND: Hyperinsulinemia is independently associated with increased risk and mortality of pancreatic cancer. We recently reported that genetically reduced insulin production resulted in ~ 50% suppression of pancreatic intraepithelial neoplasia (PanIN) precancerous lesions in mice. However, only female mice remained normoglycemic, and only the gene dosage of the rodent-specific Ins1 alleles was tested in our previous model. Moreover, we did not delve into the molecular and cellular mechanisms associated with modulating hyperinsulinemia. METHODS: We studied how reduced Ins2 gene dosage affects PanIN lesion development in both male and female Ptf1a(CreER);Kras(LSL-G12D) mice lacking the rodent-specific Ins1 gene (Ins1(-/-)). We generated control mice having two alleles of the wild-type Ins2 gene (Ptf1a(CreER);Kras(LSL-G12D);Ins1(-/-);Ins2(+/+)) and experimental mice having one allele of Ins2 gene (Ptf1a(CreER);Kras(LSL-G12D);Ins1(-/-);Ins2(+/-)). We then performed thorough histopathological analyses and single-cell transcriptomics for both genotypes and sexes. RESULTS: High-fat diet–induced hyperinsulinemia was transiently or modestly reduced in female and male mice, respectively, with only one allele of Ins2. This occurred without dramatically affecting glucose tolerance. Genetic reduction of insulin production resulted in mice with a tendency for less PanIN and acinar-to-ductal metaplasia (ADM) lesions. Using single-cell transcriptomics, we found hyperinsulinemia affected multiple cell types in the pancreas, with the most statistically significant effects on local immune cell types that were highly represented in our sampled cell population. Specifically, hyperinsulinemia modulated pathways associated with protein translation, MAPK-ERK signaling, and PI3K-AKT signaling, which were changed in epithelial cells and subsets of immune cells. CONCLUSIONS: These data suggest a potential role for the immune microenvironment in hyperinsulinemia-driven PanIN development. Together with our previous work, we propose that mild suppression of insulin levels may be useful in preventing pancreatic cancer by acting on multiple cell types. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40170-022-00282-z. |
format | Online Article Text |
id | pubmed-8862319 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-88623192022-02-23 Effects of hyperinsulinemia on pancreatic cancer development and the immune microenvironment revealed through single-cell transcriptomics Zhang, Anni M. Y. Chu, Ken H. Daly, Brian F. Ruiter, Titine Dou, Yan Yang, Jenny C. C. de Winter, Twan J. J. Chhuor, Justin Wang, Su Flibotte, Stephane Zhao, Yiwei Bernie Hu, Xiaoke Li, Hong Rideout, Elizabeth J. Schaeffer, David F. Johnson, James D. Kopp, Janel L. Cancer Metab Research BACKGROUND: Hyperinsulinemia is independently associated with increased risk and mortality of pancreatic cancer. We recently reported that genetically reduced insulin production resulted in ~ 50% suppression of pancreatic intraepithelial neoplasia (PanIN) precancerous lesions in mice. However, only female mice remained normoglycemic, and only the gene dosage of the rodent-specific Ins1 alleles was tested in our previous model. Moreover, we did not delve into the molecular and cellular mechanisms associated with modulating hyperinsulinemia. METHODS: We studied how reduced Ins2 gene dosage affects PanIN lesion development in both male and female Ptf1a(CreER);Kras(LSL-G12D) mice lacking the rodent-specific Ins1 gene (Ins1(-/-)). We generated control mice having two alleles of the wild-type Ins2 gene (Ptf1a(CreER);Kras(LSL-G12D);Ins1(-/-);Ins2(+/+)) and experimental mice having one allele of Ins2 gene (Ptf1a(CreER);Kras(LSL-G12D);Ins1(-/-);Ins2(+/-)). We then performed thorough histopathological analyses and single-cell transcriptomics for both genotypes and sexes. RESULTS: High-fat diet–induced hyperinsulinemia was transiently or modestly reduced in female and male mice, respectively, with only one allele of Ins2. This occurred without dramatically affecting glucose tolerance. Genetic reduction of insulin production resulted in mice with a tendency for less PanIN and acinar-to-ductal metaplasia (ADM) lesions. Using single-cell transcriptomics, we found hyperinsulinemia affected multiple cell types in the pancreas, with the most statistically significant effects on local immune cell types that were highly represented in our sampled cell population. Specifically, hyperinsulinemia modulated pathways associated with protein translation, MAPK-ERK signaling, and PI3K-AKT signaling, which were changed in epithelial cells and subsets of immune cells. CONCLUSIONS: These data suggest a potential role for the immune microenvironment in hyperinsulinemia-driven PanIN development. Together with our previous work, we propose that mild suppression of insulin levels may be useful in preventing pancreatic cancer by acting on multiple cell types. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40170-022-00282-z. BioMed Central 2022-02-21 /pmc/articles/PMC8862319/ /pubmed/35189981 http://dx.doi.org/10.1186/s40170-022-00282-z Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Zhang, Anni M. Y. Chu, Ken H. Daly, Brian F. Ruiter, Titine Dou, Yan Yang, Jenny C. C. de Winter, Twan J. J. Chhuor, Justin Wang, Su Flibotte, Stephane Zhao, Yiwei Bernie Hu, Xiaoke Li, Hong Rideout, Elizabeth J. Schaeffer, David F. Johnson, James D. Kopp, Janel L. Effects of hyperinsulinemia on pancreatic cancer development and the immune microenvironment revealed through single-cell transcriptomics |
title | Effects of hyperinsulinemia on pancreatic cancer development and the immune microenvironment revealed through single-cell transcriptomics |
title_full | Effects of hyperinsulinemia on pancreatic cancer development and the immune microenvironment revealed through single-cell transcriptomics |
title_fullStr | Effects of hyperinsulinemia on pancreatic cancer development and the immune microenvironment revealed through single-cell transcriptomics |
title_full_unstemmed | Effects of hyperinsulinemia on pancreatic cancer development and the immune microenvironment revealed through single-cell transcriptomics |
title_short | Effects of hyperinsulinemia on pancreatic cancer development and the immune microenvironment revealed through single-cell transcriptomics |
title_sort | effects of hyperinsulinemia on pancreatic cancer development and the immune microenvironment revealed through single-cell transcriptomics |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8862319/ https://www.ncbi.nlm.nih.gov/pubmed/35189981 http://dx.doi.org/10.1186/s40170-022-00282-z |
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