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HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer

51 Pages Posted: 6 Aug 2019 Sneak Peek Status: Review Complete

See all articles by Holly Brunton

Holly Brunton

University of Glasgow - Institute of Cancer Sciences

Giuseppina Caligiuri

University of Glasgow - Institute of Cancer Sciences

Richard Cunningham

University of Glasgow - Institute of Cancer Sciences

Rosie Upstill-Goddard

University of Glasgow - Institute of Cancer Sciences

Ulla-Maja Bailey

University of Glasgow - Institute of Cancer Sciences

Ian M. Garner

Imperial College London - Epigenetics Unit

Craig Nourse

Cancer Research UK Beatson Institute

Stephan Dreyer

University of Glasgow - Institute of Cancer Sciences

Marc Jones

Queen Elizabeth University Hospital

Kim Moran-Jones

Queen Elizabeth University Hospital

Derek W. Wright

University of Glasgow - Institute of Cancer Sciences

Viola Paulus-Hock

Cancer Research UK Beatson Institute

Colin Nixon

Cancer Research UK Beatson Institute

Gemma Thomson

Cancer Research UK Beatson Institute

Nigel Jamieson

University of Glasgow - Institute of Cancer Sciences

Grant A. McGregor

Cancer Research UK Beatson Institute

Lisa Evers

University of Glasgow - Institute of Cancer Sciences

Colin J. McKay

University of Glasgow - Institute of Cancer Sciences

Aditi Gulati

The Institute of Cancer Research - CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre

Rachel Brough

The Institute of Cancer Research - CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre

Ilirjana Bajrami

The Institute of Cancer Research - CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre

Stephen Pettit

The Institute of Cancer Research - CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre

Michele L. Dziubinski

University of Michigan at Ann Arbor - Department of Molecular and Integrative Physiology

Simon T. Barry

AstraZeneca Pharmaceuticals - Bioscience, Oncology, IMED Biotech Unit

Robert Grützmann

University of Erlangen-Nuremberg (FAU) - Department of Surgery

Robert Brown

Imperial College London - Epigenetics Unit

Edward Curry

Imperial College London - Epigenetics Unit

Glasgow Precision Oncology Laboratory

Australian Pancreatic Cancer Genome Initiative

Marina Pajic

The Kinghorn Cancer Centre

Elizabeth A. Musgrove

University of Glasgow - Institute of Cancer Sciences

Gloria Petersen

Mayo Clinic - College of Medicine and Science

Emma Shanks

Cancer Research UK Beatson Institute

Alan Ashworth

The Institute of Cancer Research - CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre

Howard C. Crawford

University of Michigan at Ann Arbor - Department of Molecular and Integrative Physiology

Diane M. Simeone

New York University (NYU) - Pancreatic Cancer Center

Fieke E.M. Froeling

Imperial College London - Epigenetics Unit

Christopher J. Lord

The Institute of Cancer Research - CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre

Debabrata Mukhopadhyay

Mayo Clinic - Florida - Department of Biochemistry and Molecular Biology

Christian Pilarsky

University of Erlangen-Nuremberg (FAU) - Department of Surgery

Sean E. Grimmond

University of Melbourne - Centre for Cancer Research

Jennifer P. Morton

University of Glasgow - Institute of Cancer Sciences

Owen J. Sansom

Beatson Institute for Cancer Research

David K. Chang

University of Glasgow - Institute of Cancer Sciences

Peter Bailey

Beatson Institute for Cancer Research; University of Glasgow - Wolfson Wohl Cancer Research Centre

Andrew V. Biankin

University of Glasgow - Wolfson Wohl Cancer Research Centre

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Abstract

The identification of molecularly defined subgroups of Pancreatic ductal Adenocarcinoma (PDAC) has the potential to transform clinical practice. There is now a growing consensus that PDAC can be divided into transcriptomic subtypes with 2 broad linages referred to as Classical (Pancreatic) and Squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal linage specification, HNF4A and GATA6, switch metabolic profiles from Classical (Pancreatic) to predominantly Squamous, with GSK3B a key regulator of glycolysis. Pharmacological inhibition of GSK3B results in selective sensitivity in the Squamous subtype, however a subset of these Squamous PDCLs acquired rapid drug tolerance. Using chromatin accessibility maps, we identify subtype specific chromatin landscapes and unique promoter usage between subpopulations of Squamous PDCLs can affect drug tolerance. Our findings demonstrate that a chromatin-based framework can be used to identify subtypes of PDAC that are indistinguishable by gene expression profiles which could refine patient selection for precision medicine.

Keywords: PDAC-subtypes, HNF4a, GATA6, metabolic-targeting, Gsk3b, distal-promoters, chromatin-landscapes, therapeutic-tolerance

Suggested Citation

Brunton, Holly and Caligiuri, Giuseppina and Cunningham, Richard and Upstill-Goddard, Rosie and Bailey, Ulla-Maja and Garner, Ian M. and Nourse, Craig and Dreyer, Stephan and Jones, Marc and Moran-Jones, Kim and Wright, Derek W. and Paulus-Hock, Viola and Nixon, Colin and Thomson, Gemma and Jamieson, Nigel and McGregor, Grant A. and Evers, Lisa and McKay, Colin J. and Gulati, Aditi and Brough, Rachel and Bajrami, Ilirjana and Pettit, Stephen and Dziubinski, Michele L. and Barry, Simon T. and Grützmann, Robert and Brown, Robert and Curry, Edward and Laboratory, Glasgow Precision Oncology and Initiative, Australian Pancreatic Cancer Genome and Pajic, Marina and Musgrove, Elizabeth A. and Petersen, Gloria and Shanks, Emma and Ashworth, Alan and Crawford, Howard C. and Simeone, Diane M. and Froeling, Fieke E.M. and Lord, Christopher J. and Mukhopadhyay, Debabrata and Pilarsky, Christian and Grimmond, Sean E. and Morton, Jennifer P. and Sansom, Owen J. and Chang, David K. and Bailey, Peter and Biankin, Andrew V., HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer (August 2, 2019). CELL-REPORTS-D-19-02927. Available at SSRN: https://ssrn.com/abstract=3430714 or http://dx.doi.org/10.2139/ssrn.3430714
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Holly Brunton (Contact Author)

University of Glasgow - Institute of Cancer Sciences ( email )

Glasgow, Scotland G12 8LE
United Kingdom

Giuseppina Caligiuri

University of Glasgow - Institute of Cancer Sciences ( email )

Glasgow, Scotland G12 8LE
United Kingdom

Richard Cunningham

University of Glasgow - Institute of Cancer Sciences

Glasgow, Scotland G12 8LE
United Kingdom

Rosie Upstill-Goddard

University of Glasgow - Institute of Cancer Sciences ( email )

Glasgow, Scotland G12 8LE
United Kingdom

Ulla-Maja Bailey

University of Glasgow - Institute of Cancer Sciences ( email )

Glasgow, Scotland G12 8LE
United Kingdom

Ian M. Garner

Imperial College London - Epigenetics Unit

Hammersmith Campus, Du Cane Road
London, W12 ONN
United Kingdom

Craig Nourse

Cancer Research UK Beatson Institute ( email )

Switchback Road
Glasgow, G61 1BD
United Kingdom

Stephan Dreyer

University of Glasgow - Institute of Cancer Sciences

Glasgow, Scotland G12 8LE
United Kingdom

Marc Jones

Queen Elizabeth University Hospital

Glasgow, G51 4TF
United Kingdom

Kim Moran-Jones

Queen Elizabeth University Hospital ( email )

Glasgow, G51 4TF
United Kingdom

Derek W. Wright

University of Glasgow - Institute of Cancer Sciences ( email )

Glasgow, Scotland G12 8LE
United Kingdom

Viola Paulus-Hock

Cancer Research UK Beatson Institute ( email )

Switchback Road
Glasgow, G61 1BD
United Kingdom

Colin Nixon

Cancer Research UK Beatson Institute

Switchback Road
Glasgow, G61 1BD
United Kingdom

Gemma Thomson

Cancer Research UK Beatson Institute

Switchback Road
Glasgow, G61 1BD
United Kingdom

Nigel Jamieson

University of Glasgow - Institute of Cancer Sciences ( email )

Glasgow, Scotland G12 8LE
United Kingdom

Grant A. McGregor

Cancer Research UK Beatson Institute

Switchback Road
Glasgow, G61 1BD
United Kingdom

Lisa Evers

University of Glasgow - Institute of Cancer Sciences

Glasgow, Scotland G12 8LE
United Kingdom

Colin J. McKay

University of Glasgow - Institute of Cancer Sciences

Glasgow, Scotland G12 8LE
United Kingdom

Aditi Gulati

The Institute of Cancer Research - CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre

Fulham Road, SW3 6JB
United Kingdom

Rachel Brough

The Institute of Cancer Research - CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre

Fulham Road, SW3 6JB
United Kingdom

Ilirjana Bajrami

The Institute of Cancer Research - CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre

Fulham Road, SW3 6JB
United Kingdom

Stephen Pettit

The Institute of Cancer Research - CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre

Fulham Road, SW3 6JB
United Kingdom

Michele L. Dziubinski

University of Michigan at Ann Arbor - Department of Molecular and Integrative Physiology

500 S. State Street
Ann Arbor, MI 48109
United States

Simon T. Barry

AstraZeneca Pharmaceuticals - Bioscience, Oncology, IMED Biotech Unit

Cambridge
United Kingdom

Robert Grützmann

University of Erlangen-Nuremberg (FAU) - Department of Surgery

Erlangen
Germany

Robert Brown

Imperial College London - Epigenetics Unit

Hammersmith Campus, Du Cane Road
London, W12 ONN
United Kingdom

Edward Curry

Imperial College London - Epigenetics Unit

Hammersmith Campus, Du Cane Road
London, W12 ONN
United Kingdom

Marina Pajic

The Kinghorn Cancer Centre

370 Victoria Street
Sydnet, NSW 2010
Australia

Elizabeth A. Musgrove

University of Glasgow - Institute of Cancer Sciences

Glasgow, Scotland G12 8LE
United Kingdom

Gloria Petersen

Mayo Clinic - College of Medicine and Science ( email )

200 First Street S.W
Rochester, MN 55905
United States

Emma Shanks

Cancer Research UK Beatson Institute

Switchback Road
Glasgow, G61 1BD
United Kingdom

Alan Ashworth

The Institute of Cancer Research - CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre

Fulham Road, SW3 6JB
United Kingdom

Howard C. Crawford

University of Michigan at Ann Arbor - Department of Molecular and Integrative Physiology

500 S. State Street
Ann Arbor, MI 48109
United States

Diane M. Simeone

New York University (NYU) - Pancreatic Cancer Center

New York, NY 10016
United States

Fieke E.M. Froeling

Imperial College London - Epigenetics Unit

Hammersmith Campus, Du Cane Road
London, W12 ONN
United Kingdom

Christopher J. Lord

The Institute of Cancer Research - CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre

Fulham Road, SW3 6JB
United Kingdom

Debabrata Mukhopadhyay

Mayo Clinic - Florida - Department of Biochemistry and Molecular Biology

Jacksonville, FL 32224
United States

Christian Pilarsky

University of Erlangen-Nuremberg (FAU) - Department of Surgery

Erlangen
Germany

Sean E. Grimmond

University of Melbourne - Centre for Cancer Research

Victoria, 3010
Australia

Jennifer P. Morton

University of Glasgow - Institute of Cancer Sciences

Glasgow, Scotland G12 8LE
United Kingdom

Owen J. Sansom

Beatson Institute for Cancer Research ( email )

Switchback Rd
Bearsden, Glasgow G61 1BD
United Kingdom

David K. Chang

University of Glasgow - Institute of Cancer Sciences

Glasgow, Scotland G12 8LE
United Kingdom

Peter Bailey

Beatson Institute for Cancer Research ( email )

Switchback Rd
Bearsden, Glasgow G61 1BD
United Kingdom

University of Glasgow - Wolfson Wohl Cancer Research Centre ( email )

Garscube Estate, Switchback Road
Scotland, Glasgow
United Kingdom

Andrew V. Biankin

University of Glasgow - Wolfson Wohl Cancer Research Centre ( email )

Garscube Estate, Switchback Road
Scotland, Glasgow
United Kingdom

No contact information is available for Glasgow Precision Oncology Laboratory
No contact information is available for Australian Pancreatic Cancer Genome Initiative

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