Open AccessSingle-cell analyses unravel cell type–specific responses to a vitamin D analog in prostatic precancerous lesions
Author(s) -
Mohamed A. Abu el Maaty,
Élise Grelet,
Céline Keime,
AnnaIsavella Rerra,
Justine Gantzer,
C. Emprou,
Julie Terzic,
Régis Lutzing,
JeanMarc Bornert,
Gilles Laverny,
Daniel Metzger
Publication year - 2021
Publication title -
science advances
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.928
H-Index - 146
ISSN - 2375-2548
DOI - 10.1126/sciadv.abg5982
Subject(s) - stromal cell , cancer research , intraepithelial neoplasia , vitamin d and neurology , prostate cancer , cell , extracellular matrix , prostate , biology , pten , cancer , medicine , microbiology and biotechnology , signal transduction , endocrinology , pi3k/akt/mtor pathway , biochemistry
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.