期刊
SCIENCE ADVANCES
卷 7, 期 31, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abg5982
关键词
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资金
- CNRS
- INSERM
- Universite de Strasbourg
- Institut National du Cancer (INCa) [PLBIO16-079/2016-153]
- Fondation ARC pour la Recherche sur le Cancer
- Ligue Contre le Cancer
- Alsace Contre le Cancer
- Association pour la Recherche sur les Tumeurs de la Prostate
- Canceropole Est
- Fondation pour la Recherche Medicale grant [EQU201903007800]
- Centre d'Ingenierie Moleculaire Europeen
- French state funds through the Agence Nationale de la Recherche [ANR-10-LABX-0030-INRT, ANR-10-IDEX-0002-02]
- Ministere de l'enseignement superieur et de la recherche
- IGBMC International PhD Program fellowship - LabEx INRT funds
- Plan Cancer 2014-2019
- Ecole de l'Institut National de la Sante et de la Recherche Medicale Liliane Bettencourt
- Faculte de Medecine de Strasbourg
The study found that Gemini-72 induced apoptosis in senescent prostatic intraepithelial neoplasia cells, normalized extracellular matrix remodeling by stromal fibroblasts, and reduced the infiltration of immunosuppressive myeloid-derived cells. Single-cell RNA-sequencing analysis showed that while a subset of luminal cells were lost after treatment, antiapoptotic pathways were induced in persistent luminal cells.
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.
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