Lactate-mediated epigenetic reprogramming regulates formation of human pancreatic cancer-associated fibroblasts
- Albert Einstein College of Medicine, United States
- University of Michigan, United States
- Rutgers University, United States
- University of Texas MD Anderson Cancer Center, United States
- Cleveland Clinic, United States
- University of Nebraska Medical Center, United States
- Johns Hopkins University, United States
- GenomeRxUs LLC, United States
Abstract
Even though pancreatic ductal adenocarcinoma (PDAC) is associated with fibrotic stroma, the molecular pathways regulating the formation of cancer associated fibroblasts (CAFs) are not well elucidated. An epigenomic analysis of patient-derived and de-novo generated CAFs demonstrated widespread loss of cytosine methylation that was associated with overexpression of various inflammatory transcripts including CXCR4. Co-culture of neoplastic cells with CAFs led to increased invasiveness that was abrogated by inhibition of CXCR4. Metabolite tracing revealed that lactate produced by neoplastic cells leads to increased production of alpha-ketoglutarate (aKG) within mesenchymal stem cells (MSCs). In turn, aKG mediated activation of the demethylase TET enzyme led to decreased cytosine methylation and increased hydroxymethylation during de novo differentiation of MSCs to CAF. Co-injection of neoplastic cells with TET-deficient MSCs inhibited tumor growth in vivo. Thus, in PDAC, a tumor-mediated lactate flux is associated with widespread epigenomic reprogramming that is seen during CAF formation.
Data availability
Sequencing data have been deposited in GEO under accession code GSE135218.
Article and author information
Author details
Matthias Bartenstein
Funding
Einstein Training Program in Stem Cell Research (C34874GG)
- Tushar D Bhagat
National Cancer Institute (T32 CA200561)
- Dagny Von Ahrens
National Cancer Institute (R01CA227622)
- Deepak Nagrath
National Cancer Institute (R01CA222251)
- Deepak Nagrath
National Cancer Institute (R01CA204969)
- Deepak Nagrath
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Ralph DeBerardinis, UT Southwestern Medical Center, United States
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC no. 20181208) protocols of the Albert Einstein College of Medicine.
Version history
- Received: August 21, 2019
- Accepted: October 27, 2019
- Accepted Manuscript published: October 30, 2019 (version 1)
- Accepted Manuscript updated: November 1, 2019 (version 2)
- Version of Record published: November 22, 2019 (version 3)
Copyright
© 2019, Bhagat et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Lactate-mediated epigenetic reprogramming regulates formation of human pancreatic cancer-associated fibroblasts
eLife 8:e50663.
https://doi.org/10.7554/eLife.50663
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