Abstract

As a highly heterogeneous tumor, pancreatic ductal adenocarcinoma (PDAC) exhibits non-uniform responses to therapies across subtypes. Overcoming therapeutic resistance stemming from this heterogeneity remains a significant challenge. Here, we report that Vitamin D-resistant PDAC cells hijacked Vitamin D signaling to promote tumor progression, whereas epigenetic priming with glyceryl triacetate (GTA) and 5-Aza-2′-deoxycytidine (5-Aza) overcame Vitamin D resistance and shifted the transcriptomic phenotype of PDAC toward a Vitamin D-susceptible state. Increasing overall H3K27 acetylation with GTA and reducing overall DNA methylation with 5-Aza not only elevated the Vitamin D receptor (VDR) expression but also reprogrammed the Vitamin D-responsive genes. Consequently, Vitamin D inhibited cell viability and migration in the epigenetically primed PDAC cells by activating genes involved in apoptosis as well as genes involved in negative regulation of cell proliferation and migration, while the opposite effect of Vitamin D was observed in unprimed cells. Studies in genetically engineered mouse PDAC cells further validated the effects of epigenetic priming for enhancing the anti-tumor activity of Vitamin D. Using gain- and loss-of-function experiments, we further demonstrated that VDR expression was necessary but not sufficient for activating the favorable transcriptomic phenotype in respond to Vitamin D treatment in PDAC, highlighting that both the VDR and Vitamin D-responsive genes were prerequisites for Vitamin D response. These data reveal a previously undefined mechanism in which epigenetic state orchestrates the expression of both VDR and Vitamin D-responsive genes and determines the therapeutic response to Vitamin D in PDAC.

Details

Title
Epigenetic priming targets tumor heterogeneity to shift transcriptomic phenotype of pancreatic ductal adenocarcinoma towards a Vitamin D susceptible state
Author
He, Bo 1   VIAFID ORCID Logo  ; Stoffel, Lauren 1 ; He, Clifford Jiajun 1 ; Cho, Kumsun 1 ; Li, Albert M. 2 ; Jiang, Haowen 1   VIAFID ORCID Logo  ; Flowers, Brittany M. 1 ; Nguyen, Kha The 1   VIAFID ORCID Logo  ; Wang, Kelly Wen 1 ; Zhao, Audrey Yixin 1 ; Zhou, Meng-Ning 1 ; Ferreira, Sofia 1   VIAFID ORCID Logo  ; Attardi, Laura D. 3   VIAFID ORCID Logo  ; Ye, Jiangbin 4   VIAFID ORCID Logo 

 Stanford University School of Medicine, Department of Radiation Oncology, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
 Stanford University School of Medicine, Department of Radiation Oncology, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956); Stanford University School of Medicine, Cancer Biology Program, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
 Stanford University School of Medicine, Department of Radiation Oncology, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956); Stanford University School of Medicine, Cancer Biology Program, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956); Stanford University School of Medicine, Stanford Cancer Institute, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956); Stanford University School of Medicine, Department of Genetics, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
 Stanford University School of Medicine, Department of Radiation Oncology, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956); Stanford University School of Medicine, Cancer Biology Program, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956); Stanford University School of Medicine, Stanford Cancer Institute, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
Pages
89
Publication year
2024
Publication date
Jan 2024
Publisher
Springer Nature B.V.
e-ISSN
20414889
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2918400415
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.