---
title: "Vitamin D (VDR/RXR) signaling limits platinum-induced ovarian cancer stem cell plasticity"
id: "biorxiv-6-activation-of-vitamin-d-signaling-suppresses-platinum-induced-ovarian-cancer"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-6-activation-of-vitamin-d-signaling-suppresses-platinum-induced-ovarian-cancer"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.22.753468v1?rss=1"
published_at: "2026-09-23T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Vitamin D (VDR/RXR) signaling limits platinum-induced ovarian cancer stem cell plasticity
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-6-activation-of-vitamin-d-signaling-suppresses-platinum-induced-ovarian-cancer
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.22.753468v1?rss=1)
- **Published At:** 2026-09-23T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- Platinum-based chemotherapy (cisplatin) initially reduces tumor burden in advanced-stage high grade serous ovarian cancer (HGSC) but most tumors recur due to acquired resistance driven by ovarian cancer stem cells (**OCSCs**). - The study found that cisplatin both enriches pre-existing OCSCs and promotes conversion of ALDH- cells into **ALDH+** OCSC-like cells, indicating chemotherapy-induced cellular plasticity contributes to OCSC expansion. - Conversion to ALDH+ cells after cisplatin exposure was associated with activation of nuclear receptor signaling pathways, notably **vitamin D receptor (VDR/RXR)** and retinoic acid receptor (RAR/RXR) signaling. - Pharmacologic activation of **VDR/RXR signaling with vitamin D** reduced stemness phenotypes and suppressed the cisplatin-induced conversion to ALDH+ cells in experimental models. - Combining vitamin D with cisplatin decreased tumor volume in vivo more than either treatment alone, supporting a potential therapeutic benefit of targeting VDR/RXR during platinum therapy. - In contrast, cisplatin increased **RAR/RXR** signaling, suggesting distinct ligand-dependent nuclear receptor pathways differentially influence OCSC plasticity. - The data indicate platinum chemotherapy can actively induce acquisition of stem-like properties, and that modulation of **VDR/RXR** signaling is a candidate mechanism to restrain OCSC plasticity and potentially improve platinum responses. - This report is a preprint; it has not been peer reviewed. Specific experimental details, cohort sizes, dosing regimens, and statistical outcomes were not reported in the source abstract and would require consulting the full preprint for complete methods and data.
## Clinical Analysis & Structured Key Points
Activation of vitamin D signaling suppresses platinum-induced ovarian cancer stem cell plasticity | bioRxiv Skip to main content New Results Activation of vitamin D signaling suppresses platinum-induced ovarian cancer stem cell plasticity Tara X Metcalfe , Sophie Xanders , Renee A Kinne , Saranya Rajendran , Shu Zhang , Peter C Hollenhorst , View ORCID Profile Alexandre Gaspar-Maia , View ORCID Profile Heather M O'Hagan , Kenneth P. Nephew doi: https://doi.org/10.64898/2026.09.22.753468 Tara X Metcalfe 1 Indiana University School of Medicine; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sophie Xanders 1 Indiana University School of Medicine; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Renee A Kinne 1 Indiana University School of Medicine; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Saranya Rajendran 1 Indiana University School of Medicine; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Shu Zhang 1 Indiana University School of Medicine; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Peter C Hollenhorst 1 Indiana University School of Medicine; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alexandre Gaspar-Maia 2 Mayo Clinic Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Alexandre Gaspar-Maia Heather M O'Hagan 1 Indiana University School of Medicine; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Heather M O'Hagan Kenneth P. Nephew 1 Indiana University School of Medicine; Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: knephew{at}iu.edu Abstract Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Advanced-stage high grade serous ovarian cancer (HGSC) initially responds to platinum-based chemotherapy; however, most HGSC tumors recur and develop chemotherapy-resistance, making recurrent ovarian cancer (OC) a fatal disease. Ovarian cancer stem cells (OCSCs), a subpopulation of cells capable of surviving treatment and repopulating tumors, contribute to disease relapse, and understanding the mechanisms(s) responsible for OCSC survival is critical for developing strategies to overcome acquired resistance and prevent tumor recurrence. However, whether platinum-induced OCSC enrichment results from the selection of pre-existing OCSCs or chemotherapy-induced cellular plasticity, and the molecular mechanisms underlying these processes, remain poorly understood. Here, we demonstrated that cisplatin treatment not only enriched for OCSCs but promoted the conversion of ALDH- cells to ALDH+ cells, revealing chemotherapy-induced plasticity as a potential mechanism for OCSC expansion. This conversion was associated with nuclear receptor signaling pathways, vitamin D receptor signaling (VDR/RXR) and retinoic acid receptor signaling (RAR/RXR). Importantly, activation of VDR/RXR signaling with vitamin D reduced stemness phenotypes and the cisplatin induced conversion to ALDH+ cells. In addition, vitamin D combined with cisplatin decreased tumor volume in vivo compared to either treatment alone. In contrast, cisplatin treatment increased RAR/RXR signaling, supporting an associative role for ligand-dependent nuclear receptor signaling in OCSC plasticity. Together, these findings reveal that platinum chemotherapy can actively promote the acquisition of stem-like properties and identifies VDR/RXR signaling as a potential regulatory mechanism of OCSC plasticity. Targeting this pathway with vitamin D may provide a therapeutic strategy to target OCSCs and improve responses to platinum-based chemotherapy. Competing Interest Statement The authors have declared no competing interest. Footnotes https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE336228 Funder Information Declared Department of Defense Ovarian Cancer Research Program , W81XWH-21-1-0284 , P30CA082709-25 Van Andel Research Institute – Stand Up To Cancer Epigenetics Dream Team Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Back to top Previous Next Posted September 23, 2026. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Activation of vitamin D signaling suppresses platinum-induced ovarian cancer stem cell plasticity Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Activation of vitamin D signaling suppresses platinum-induced ovarian cancer stem cell plasticity Tara X Metcalfe , Sophie Xanders , Renee A Kinne , Saranya Rajendran , Shu Zhang , Peter C Hollenhorst , Alexandre Gaspar-Maia , Heather M O'Hagan , Kenneth P. Nephew bioRxiv 2026.09.22.753468; doi: https://doi.org/10.64898/2026.09.22.753468 Share This Article: Copy Citation Tools Activation of vitamin D signaling suppresses platinum-induced ovarian cancer stem cell plasticity Tara X Metcalfe , Sophie Xanders , Renee A Kinne , Saranya Rajendran , Shu Zhang , Peter C Hollenhorst , Alexandre Gaspar-Maia , Heather M O'Hagan , Kenneth P. 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