Authors

Tushar D. Bhagat, Albert Einstein College of Medicine
Dagny Von Ahrens, Albert Einstein College of Medicine
Meelad Dawlaty, Albert Einstein College of Medicine
Yiyu Zou, Albert Einstein College of Medicine
Joelle Baddour, University of Michigan - Ann Arbor
Abhinav Achreja, University of Michigan - Ann Arbor
Hongyun Zhao, University of Michigan - Ann Arbor
Lifeng Yang, University of Michigan - Ann Arbor
Brijesh Patel, Rutgers University - New Brunswick/Piscataway
Changsoo Kwak, The University of Texas MD Anderson Cancer Center
Gaurav S. Choudhary, Albert Einstein College of Medicine
Shanisha Gordon-Mitchell, Albert Einstein College of Medicine
Srinivas Aluri, Albert Einstein College of Medicine
Sanchari Bhattacharyya, Albert Einstein College of Medicine
Srabani Sahu, Albert Einstein College of Medicine
Yiting Yu, Albert Einstein College of Medicine
Matthias Bartenstein, Albert Einstein College of Medicine
Orsi Giricz, Albert Einstein College of Medicine
Masako Suzuki, Albert Einstein College of Medicine
Davendra Sohal, Cleveland Clinic
Sonal Gupta, The University of Texas MD Anderson Cancer Center
Paola A. Guerrero, The University of Texas MD Anderson Cancer Center
Surinder K. Batra, University of Nebraska Medical CenterFollow
Michael Goggins, Johns Hopkins University
Ulrich Steidl, Albert Einstein College of Medicine
John Greally, Albert Einstein College of Medicine
Beamon Agarwal, GenomeRxUs LLC
Kith Pradhan, Albert Einstein College of Medicine
Debabrata Banerjee, Rutgers University - New Brunswick/Piscataway
Deepak Nagrath, University of Michigan - Ann Arbor
Anirban Maitra, The University of Texas MD Anderson Cancer Center
Amit Verma, Albert Einstein College of Medicine

Document Type

Article

Journal Title

eLife

Publication Date

2019

Volume

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.

ISSN

2050-084X

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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