Single-cell analyses unravel cell type–specific responses to a vitamin D analog in prostatic precancerous lesions
Epidemiological data have linked vitamin D deficiency to the onset and severity of various cancers, including prostate cancer, and although in vitro studies have demonstrated anticancer activities for vitamin D, clinical trials provided conflicting results. To determine the impact of vitamin D signa...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Association for the Advancement of Science
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324049/ https://www.ncbi.nlm.nih.gov/pubmed/34330705 http://dx.doi.org/10.1126/sciadv.abg5982 |
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author | Abu el Maaty, Mohamed A. Grelet, Elise Keime, Céline Rerra, Anna-Isavella Gantzer, Justine Emprou, Camille Terzic, Julie Lutzing, Régis Bornert, Jean-Marc Laverny, Gilles Metzger, Daniel |
author_facet | Abu el Maaty, Mohamed A. Grelet, Elise Keime, Céline Rerra, Anna-Isavella Gantzer, Justine Emprou, Camille Terzic, Julie Lutzing, Régis Bornert, Jean-Marc Laverny, Gilles Metzger, Daniel |
author_sort | Abu el Maaty, Mohamed A. |
collection | PubMed |
description | Epidemiological data have linked vitamin D deficiency to the onset and severity of various cancers, including prostate cancer, and although in vitro studies have demonstrated anticancer activities for vitamin D, clinical trials provided conflicting results. To determine the impact of vitamin D signaling on prostatic precancerous lesions, we treated genetically engineered Pten((i)pe−/−) mice harboring prostatic intraepithelial neoplasia (PIN) with Gemini-72, a vitamin D analog with reported anticancer activities. We show that this analog induces apoptosis in senescent PINs, normalizes extracellular matrix remodeling by stromal fibroblasts, and reduces the prostatic infiltration of immunosuppressive myeloid-derived suppressor cells. Moreover, single-cell RNA-sequencing analysis demonstrates that while a subset of luminal cells expressing Krt8, Krt4, and Tacstd2 (termed luminal-C cells) is lost by such a treatment, antiapoptotic pathways are induced in persistent luminal-C cells. Therefore, our findings delineate the distinct responses of PINs and the microenvironment to Gemini-72, and shed light on mechanisms that limit treatment’s efficacy. |
format | Online Article Text |
id | pubmed-8324049 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-83240492021-08-10 Single-cell analyses unravel cell type–specific responses to a vitamin D analog in prostatic precancerous lesions Abu el Maaty, Mohamed A. Grelet, Elise Keime, Céline Rerra, Anna-Isavella Gantzer, Justine Emprou, Camille Terzic, Julie Lutzing, Régis Bornert, Jean-Marc Laverny, Gilles Metzger, Daniel Sci Adv Research Articles Epidemiological data have linked vitamin D deficiency to the onset and severity of various cancers, including prostate cancer, and although in vitro studies have demonstrated anticancer activities for vitamin D, clinical trials provided conflicting results. To determine the impact of vitamin D signaling on prostatic precancerous lesions, we treated genetically engineered Pten((i)pe−/−) mice harboring prostatic intraepithelial neoplasia (PIN) with Gemini-72, a vitamin D analog with reported anticancer activities. We show that this analog induces apoptosis in senescent PINs, normalizes extracellular matrix remodeling by stromal fibroblasts, and reduces the prostatic infiltration of immunosuppressive myeloid-derived suppressor cells. Moreover, single-cell RNA-sequencing analysis demonstrates that while a subset of luminal cells expressing Krt8, Krt4, and Tacstd2 (termed luminal-C cells) is lost by such a treatment, antiapoptotic pathways are induced in persistent luminal-C cells. Therefore, our findings delineate the distinct responses of PINs and the microenvironment to Gemini-72, and shed light on mechanisms that limit treatment’s efficacy. American Association for the Advancement of Science 2021-07-30 /pmc/articles/PMC8324049/ /pubmed/34330705 http://dx.doi.org/10.1126/sciadv.abg5982 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Abu el Maaty, Mohamed A. Grelet, Elise Keime, Céline Rerra, Anna-Isavella Gantzer, Justine Emprou, Camille Terzic, Julie Lutzing, Régis Bornert, Jean-Marc Laverny, Gilles Metzger, Daniel Single-cell analyses unravel cell type–specific responses to a vitamin D analog in prostatic precancerous lesions |
title | Single-cell analyses unravel cell type–specific responses to a vitamin D analog in prostatic precancerous lesions |
title_full | Single-cell analyses unravel cell type–specific responses to a vitamin D analog in prostatic precancerous lesions |
title_fullStr | Single-cell analyses unravel cell type–specific responses to a vitamin D analog in prostatic precancerous lesions |
title_full_unstemmed | Single-cell analyses unravel cell type–specific responses to a vitamin D analog in prostatic precancerous lesions |
title_short | Single-cell analyses unravel cell type–specific responses to a vitamin D analog in prostatic precancerous lesions |
title_sort | single-cell analyses unravel cell type–specific responses to a vitamin d analog in prostatic precancerous lesions |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324049/ https://www.ncbi.nlm.nih.gov/pubmed/34330705 http://dx.doi.org/10.1126/sciadv.abg5982 |
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