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 Alluri; Sanchari Bhattacharyya; Srabani Sahu; Yiting Yu; Matthias Bartenstein; Orsi Giricz; Masako Suzuki; Davendra Sohal; Sonal Gupta; Paola Guerrero; Surinder Batra; Michael Goggins; Ulrich Steidl; John Greally; Beamon Agarwal; Kith Pradhan; Debabrata Banerjee; Deepak Nagrath; Anirban Maitra; Amit Verma

doi:10.7554/eLife.50663

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 Alluri, Sanchari Bhattacharyya, Srabani Sahu, Yiting Yu, Matthias Bartenstein, Orsi Giricz, Masako Suzuki, Davendra SohalSonal Gupta, Paola Guerrero, Surinder Batra, Michael Goggins, Ulrich Steidl, John Greally, Beamon Agarwal, Kith Pradhan, Debabrata Banerjee, Deepak Nagrath, Anirban Maitra, Amit Verma

Research output: Contribution to journal › Article › peer-review

98 Scopus citations

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.

Original language	English (US)
Article number	e50663
Journal	eLife
Volume	8
DOIs	https://doi.org/10.7554/eLife.50663
State	Published - Oct 2019

Keywords

Epigenetics
Lactate
Pancreatic Cancer
Stroma

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.7554/eLife.50663

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Bhagat, T. D., Von Ahrens, D., Dawlaty, M., Zou, Y., Baddour, J., Achreja, A., Zhao, H., Yang, L., Patel, B., Kwak, C., Choudhary, G. S., Gordon-Mitchell, S., Alluri, S., Bhattacharyya, S., Sahu, S., Yu, Y., Bartenstein, M., Giricz, O., Suzuki, M., ... Verma, A. (2019). Lactate-mediated epigenetic reprogramming regulates formation of human pancreatic cancer-associated fibroblasts. eLife, 8, Article e50663. https://doi.org/10.7554/eLife.50663

Bhagat, TD, Von Ahrens, D, Dawlaty, M , Zou, Y, Baddour, J, Achreja, A, Zhao, H, Yang, L, Patel, B, Kwak, C, Choudhary, GS, Gordon-Mitchell, S, Alluri, S, Bhattacharyya, S, Sahu, S, Yu, Y, Bartenstein, M, Giricz, O, Suzuki, M, Sohal, D, Gupta, S, Guerrero, P, Batra, S, Goggins, M, Steidl, U , Greally, J, Agarwal, B, Pradhan, K, Banerjee, D, Nagrath, D, Maitra, A & Verma, A 2019, 'Lactate-mediated epigenetic reprogramming regulates formation of human pancreatic cancer-associated fibroblasts', eLife, vol. 8, e50663. https://doi.org/10.7554/eLife.50663

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title = "Lactate-mediated epigenetic reprogramming regulates formation of human pancreatic cancer-associated fibroblasts",

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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AU - Von Ahrens, Dagny

AU - Dawlaty, Meelad

AU - Zou, Yiyu

AU - Baddour, Joelle

AU - Achreja, Abhinav

AU - Zhao, Hongyun

AU - Yang, Lifeng

AU - Patel, Brijesh

AU - Kwak, Changsoo

AU - Choudhary, Gaurav S.

AU - Gordon-Mitchell, Shanisha

AU - Alluri, Srinivas

AU - Bhattacharyya, Sanchari

AU - Sahu, Srabani

AU - Yu, Yiting

AU - Bartenstein, Matthias

AU - Giricz, Orsi

AU - Suzuki, Masako

AU - Sohal, Davendra

AU - Gupta, Sonal

AU - Guerrero, Paola

AU - Batra, Surinder

AU - Goggins, Michael

AU - Steidl, Ulrich

AU - Greally, John

AU - Agarwal, Beamon

AU - Pradhan, Kith

AU - Banerjee, Debabrata

AU - Nagrath, Deepak

AU - Maitra, Anirban

AU - Verma, Amit

PY - 2019/10

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N2 - 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.

AB - 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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KW - Pancreatic Cancer

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Lactate-mediated epigenetic reprogramming regulates formation of human pancreatic cancer-associated fibroblasts

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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