eLife (Oct 2019)
Lactate-mediated epigenetic reprogramming regulates formation of human pancreatic cancer-associated fibroblasts
- Tushar D Bhagat,
- Dagny Von Ahrens,
- Meelad Dawlaty,
- Yiyu Zou,
- Joelle Baddour,
- Abhinav Achreja,
- Hongyun Zhao,
- Lifeng Yang,
- Brijesh Patel,
- Changsoo Kwak,
- Gaurav S Choudhary,
- Shanisha Gordon-Mitchell,
- Srinivas Aluri,
- Sanchari Bhattacharyya,
- Srabani Sahu,
- Prafulla Bhagat,
- Yiting Yu,
- Matthias Bartenstein,
- Orsi Giricz,
- Masako Suzuki,
- Davendra Sohal,
- Sonal Gupta,
- Paola A Guerrero,
- Surinder Batra,
- Michael Goggins,
- Ulrich Steidl,
- John Greally,
- Beamon Agarwal,
- Kith Pradhan,
- Debabrata Banerjee,
- Deepak Nagrath,
- Anirban Maitra,
- Amit Verma
Affiliations
- Tushar D Bhagat
- ORCiD
- Albert Einstein College of Medicine, Montefiore Medical Center, New York, United States
- Dagny Von Ahrens
- Albert Einstein College of Medicine, Montefiore Medical Center, New York, United States
- Meelad Dawlaty
- Albert Einstein College of Medicine, Montefiore Medical Center, New York, United States
- Yiyu Zou
- Albert Einstein College of Medicine, Montefiore Medical Center, New York, United States
- Joelle Baddour
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States
- Abhinav Achreja
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States
- Hongyun Zhao
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States
- Lifeng Yang
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States
- Brijesh Patel
- Rutgers University, New Brunswick, United States
- Changsoo Kwak
- Department of Pathology, Sheikh Ahmed Pancreatic Cancer Research Center, UT MD Anderson Cancer Center, Houston, United States; Department of Translational Molecular Pathology, Sheikh Ahmed Pancreatic Cancer Research Center, UT MD Anderson Cancer Center, Houston, United States
- Gaurav S Choudhary
- Albert Einstein College of Medicine, Montefiore Medical Center, New York, United States
- Shanisha Gordon-Mitchell
- Albert Einstein College of Medicine, Montefiore Medical Center, New York, United States
- Srinivas Aluri
- Albert Einstein College of Medicine, Montefiore Medical Center, New York, United States
- Sanchari Bhattacharyya
- Albert Einstein College of Medicine, Montefiore Medical Center, New York, United States
- Srabani Sahu
- Albert Einstein College of Medicine, Montefiore Medical Center, New York, United States
- Prafulla Bhagat
- Albert Einstein College of Medicine, Montefiore Medical Center, New York, United States
- Yiting Yu
- Albert Einstein College of Medicine, Montefiore Medical Center, New York, United States
- Matthias Bartenstein
- ORCiD
- Albert Einstein College of Medicine, Montefiore Medical Center, New York, United States
- Orsi Giricz
- Albert Einstein College of Medicine, Montefiore Medical Center, New York, United States
- Masako Suzuki
- Albert Einstein College of Medicine, Montefiore Medical Center, New York, United States
- Davendra Sohal
- Department of Medicine, Cleveland Clinic, Cleveland, United States
- Sonal Gupta
- Department of Pathology, Sheikh Ahmed Pancreatic Cancer Research Center, UT MD Anderson Cancer Center, Houston, United States; Department of Translational Molecular Pathology, Sheikh Ahmed Pancreatic Cancer Research Center, UT MD Anderson Cancer Center, Houston, United States
- Paola A Guerrero
- Department of Pathology, Sheikh Ahmed Pancreatic Cancer Research Center, UT MD Anderson Cancer Center, Houston, United States; Department of Translational Molecular Pathology, Sheikh Ahmed Pancreatic Cancer Research Center, UT MD Anderson Cancer Center, Houston, United States
- Surinder Batra
- University of Nebraska Medical Center, Omaha, United States
- Michael Goggins
- Johns Hopkins, Baltimore, United States
- Ulrich Steidl
- Albert Einstein College of Medicine, Montefiore Medical Center, New York, United States
- John Greally
- ORCiD
- Albert Einstein College of Medicine, Montefiore Medical Center, New York, United States
- Beamon Agarwal
- GenomeRxUs LLC, Secane, United States
- Kith Pradhan
- Albert Einstein College of Medicine, Montefiore Medical Center, New York, United States
- Debabrata Banerjee
- Rutgers University, New Brunswick, United States
- Deepak Nagrath
- ORCiD
- Biointerfaces Institute, University of Michigan, Ann Arbor, United States
- Anirban Maitra
- Department of Pathology, Sheikh Ahmed Pancreatic Cancer Research Center, UT MD Anderson Cancer Center, Houston, United States; Department of Translational Molecular Pathology, Sheikh Ahmed Pancreatic Cancer Research Center, UT MD Anderson Cancer Center, Houston, United States
- Amit Verma
- ORCiD
- Albert Einstein College of Medicine, Montefiore Medical Center, New York, United States
- DOI
- https://doi.org/10.7554/eLife.50663
- Journal volume & issue
-
Vol. 8
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.
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