HNF4A and GATA6 loss reveals therapeutically actionable subtypes in pancreatic cancer

Holly Brunton; Giuseppina Caligiuri; Richard Cunningham; Rosie Upstill-Goddard; Ulla-Maja Bailey; Ian M. Garner; Craig Nourse; Stephan Dreyer; Marc Jones; Kim Moran-Jones; Derek W. Wright; Viola Paulus-Hock; Colin Nixon; Gemma Thomson; Nigel B. Jamieson; Grant A. McGregor; Lisa Evers; Colin J. McKay; Aditi Gulati; Rachel Brough; Ilirjana Bajrami; Stephen J. Pettitt; Michele L. Dziubinski; Simon T. Barry; Robert Grützmann; Robert Brown; Edward Curry; Sarah Allison; Andrew V. Biankin; David K. Chang; Susanna L. Cook; Paul Grimwood; Shane Kelly; John F. Marshall; Brian McDade; Daniel McElroy; Donna Ramsay; Selma Rebus; Jane Hair; Paul Westwood; Nicola Williams; Fraser R. Duthie; Amber L. Johns; Amanda Mawson; Christopher J. Scarlett; Mary Anne L. Brancato; Sarah J. Rowe; Skye H. Simpson; Mona Martyn-Smith; Michelle T. Thomas; Lorraine A. Chantrill; Venessa T. Chin; Angela S. Chou; Mark J. Cowley; Jeremy L. Humphris; Ronald S. Mead; Adnan M. Nagrial; Marina Pajic; Jessica Pettit; Mark Pinese; Ilse Rooman; Jianmin Wu; Jiang Tao; Renee DiPietro; Clare Watson; Angela M. Steinmann; Hongching Lee; Rachel Wong; Andreia V. Pinho; Marc Giry-Laterrière; Roger J. Daly; Elizabeth A. Musgrove; Robert L. Sutherland; Sean M. Grimmond; Nicola Waddell; Karin S. Kassahn; David K. Miller; Peter J. Wilson; Ann Marie Patch; Sarah Song; Ivon Harliwong; Senel Idrisoglu; Ehsan Nourbakhsh; Suzanne Manning; Shivangi Wani; Milena M. Gongora; Matthew L. Anderson; Oliver Holmes; Conrad R. Leonard; Darrin F. Taylor; Scott Wood; Christina W. Xu; Kátia Nones; J. Lynn Fink; Angelika N. Christ; Timothy J. Bruxner; Nicole Cloonan; Felicity S. Newell; John V. Pearson; Michael C. Quinn; Shivashankar H. Nagaraj; Stephen H. Kazakoff; Nick M. Waddell; Keerthana Krisnan; Kelly Quek; David L. Wood; Jaswinder S. Samra; Anthony J. Gill; Nick Pavlakis; Alexander D. Guminski; Christopher W. Toon; Ray Asghari; Neil D. Merrett; null et al

doi:10.1016/j.celrep.2020.107625

HNF4A and GATA6 loss reveals therapeutically actionable subtypes in pancreatic cancer

Holly Brunton, Giuseppina Caligiuri, Richard Cunningham, Rosie Upstill-Goddard, Ulla-Maja Bailey, Ian M. Garner, Craig Nourse, Stephan Dreyer, Marc Jones, Kim Moran-Jones, Derek W. Wright, Viola Paulus-Hock, Colin Nixon, Gemma Thomson, Nigel B. Jamieson, Grant A. McGregor, Lisa Evers, Colin J. McKay, Aditi Gulati, Rachel BroughIlirjana Bajrami, Stephen J. Pettitt, Michele L. Dziubinski, Simon T. Barry, Robert Grützmann, Robert Brown, Edward Curry, Sarah Allison, Andrew V. Biankin, David K. Chang, Susanna L. Cook, Paul Grimwood, Shane Kelly, John F. Marshall, Brian McDade, Daniel McElroy, Donna Ramsay, Selma Rebus, Jane Hair, Paul Westwood, Nicola Williams, Fraser R. Duthie, Amber L. Johns, Amanda Mawson, Christopher J. Scarlett, Mary Anne L. Brancato, Sarah J. Rowe, Skye H. Simpson, Mona Martyn-Smith, Michelle T. Thomas, Lorraine A. Chantrill, Venessa T. Chin, Angela S. Chou, Mark J. Cowley, Jeremy L. Humphris, Ronald S. Mead, Adnan M. Nagrial, Marina Pajic, Jessica Pettit, Mark Pinese, Ilse Rooman, Jianmin Wu, Jiang Tao, Renee DiPietro, Clare Watson, Angela M. Steinmann, Hongching Lee, Rachel Wong, Andreia V. Pinho, Marc Giry-Laterrière, Roger J. Daly, Elizabeth A. Musgrove, Robert L. Sutherland, Sean M. Grimmond, Nicola Waddell, Karin S. Kassahn, David K. Miller, Peter J. Wilson, Ann Marie Patch, Sarah Song, Ivon Harliwong, Senel Idrisoglu, Ehsan Nourbakhsh, Suzanne Manning, Shivangi Wani, Milena M. Gongora, Matthew L. Anderson, Oliver Holmes, Conrad R. Leonard, Darrin F. Taylor, Scott Wood, Christina W. Xu, Kátia Nones, J. Lynn Fink, Angelika N. Christ, Timothy J. Bruxner, Nicole Cloonan, Felicity S. Newell, John V. Pearson, Michael C. Quinn, Shivashankar H. Nagaraj, Stephen H. Kazakoff, Nick M. Waddell, Keerthana Krisnan, Kelly Quek, David L. Wood, Jaswinder S. Samra, Anthony J. Gill, Nick Pavlakis, Alexander D. Guminski, Christopher W. Toon, Ray Asghari, Neil D. Merrett, et al

Western Sydney University

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

Abstract

Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages 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 lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3b) a key regulator of glycolysis. Pharmacological inhibition of GSK3b results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3b inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC.

Original language	English
Article number	107625
Number of pages	17
Journal	Cell Reports
Volume	31
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2020.107625
Publication status	Published - 2020

Open Access - Access Right Statement

Keywords

cancer
pancreas
pancreatic acinar cells
pancreatic duct

UN SDGs

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

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10.1016/j.celrep.2020.107625

Cite this

Brunton, H., Caligiuri, G., Cunningham, R., Upstill-Goddard, R., Bailey, U.-M., Garner, I. M., Nourse, C., Dreyer, S., Jones, M., Moran-Jones, K., Wright, D. W., Paulus-Hock, V., Nixon, C., Thomson, G., Jamieson, N. B., McGregor, G. A., Evers, L., McKay, C. J., Gulati, A., ... et al (2020). HNF4A and GATA6 loss reveals therapeutically actionable subtypes in pancreatic cancer. Cell Reports, 31(6), Article 107625. https://doi.org/10.1016/j.celrep.2020.107625

@article{975e43ca7e684a078d3f3f86828d64cc,

title = "HNF4A and GATA6 loss reveals therapeutically actionable subtypes in pancreatic cancer",

abstract = "Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages 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 lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3b) a key regulator of glycolysis. Pharmacological inhibition of GSK3b results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3b inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC.",

keywords = "cancer, pancreas, pancreatic acinar cells, pancreatic duct",

author = "Holly Brunton and Giuseppina Caligiuri and Richard Cunningham and Rosie Upstill-Goddard and Ulla-Maja Bailey and Garner, {Ian M.} and Craig Nourse and Stephan Dreyer and Marc Jones and Kim Moran-Jones and Wright, {Derek W.} and Viola Paulus-Hock and Colin Nixon and Gemma Thomson and Jamieson, {Nigel B.} and McGregor, {Grant A.} and Lisa Evers and McKay, {Colin J.} and Aditi Gulati and Rachel Brough and Ilirjana Bajrami and Pettitt, {Stephen J.} and Dziubinski, {Michele L.} and Barry, {Simon T.} and Robert Gr{\"u}tzmann and Robert Brown and Edward Curry and Sarah Allison and Biankin, {Andrew V.} and Chang, {David K.} and Cook, {Susanna L.} and Paul Grimwood and Shane Kelly and Marshall, {John F.} and Brian McDade and Daniel McElroy and Donna Ramsay and Selma Rebus and Jane Hair and Paul Westwood and Nicola Williams and Duthie, {Fraser R.} and Johns, {Amber L.} and Amanda Mawson and Scarlett, {Christopher J.} and Brancato, {Mary Anne L.} and Rowe, {Sarah J.} and Simpson, {Skye H.} and Mona Martyn-Smith and Thomas, {Michelle T.} and Chantrill, {Lorraine A.} and Chin, {Venessa T.} and Chou, {Angela S.} and Cowley, {Mark J.} and Humphris, {Jeremy L.} and Mead, {Ronald S.} and Nagrial, {Adnan M.} and Marina Pajic and Jessica Pettit and Mark Pinese and Ilse Rooman and Jianmin Wu and Jiang Tao and Renee DiPietro and Clare Watson and Steinmann, {Angela M.} and Hongching Lee and Rachel Wong and Pinho, {Andreia V.} and Marc Giry-Laterri{\`e}re and Daly, {Roger J.} and Musgrove, {Elizabeth A.} and Sutherland, {Robert L.} and Grimmond, {Sean M.} and Nicola Waddell and Kassahn, {Karin S.} and Miller, {David K.} and Wilson, {Peter J.} and Patch, {Ann Marie} and Sarah Song and Ivon Harliwong and Senel Idrisoglu and Ehsan Nourbakhsh and Suzanne Manning and Shivangi Wani and Gongora, {Milena M.} and Anderson, {Matthew L.} and Oliver Holmes and Leonard, {Conrad R.} and Taylor, {Darrin F.} and Scott Wood and Xu, {Christina W.} and K{\'a}tia Nones and Fink, {J. Lynn} and Christ, {Angelika N.} and Bruxner, {Timothy J.} and Nicole Cloonan and Newell, {Felicity S.} and Pearson, {John V.} and Quinn, {Michael C.} and Nagaraj, {Shivashankar H.} and Kazakoff, {Stephen H.} and Waddell, {Nick M.} and Keerthana Krisnan and Kelly Quek and Wood, {David L.} and Samra, {Jaswinder S.} and Gill, {Anthony J.} and Nick Pavlakis and Guminski, {Alexander D.} and Toon, {Christopher W.} and Ray Asghari and Merrett, {Neil D.} and {et al}",

year = "2020",

doi = "10.1016/j.celrep.2020.107625",

language = "English",

volume = "31",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "6",

}

Brunton, H, Caligiuri, G, Cunningham, R, Upstill-Goddard, R, Bailey, U-M, Garner, IM, Nourse, C, Dreyer, S, Jones, M, Moran-Jones, K, Wright, DW, Paulus-Hock, V, Nixon, C, Thomson, G, Jamieson, NB, McGregor, GA, Evers, L, McKay, CJ, Gulati, A, Brough, R, Bajrami, I, Pettitt, SJ, Dziubinski, ML, Barry, ST, Grützmann, R, Brown, R, Curry, E, Allison, S, Biankin, AV, Chang, DK, Cook, SL, Grimwood, P, Kelly, S, Marshall, JF, McDade, B, McElroy, D, Ramsay, D, Rebus, S, Hair, J, Westwood, P, Williams, N, Duthie, FR, Johns, AL, Mawson, A, Scarlett, CJ, Brancato, MAL, Rowe, SJ, Simpson, SH, Martyn-Smith, M, Thomas, MT, Chantrill, LA, Chin, VT, Chou, AS, Cowley, MJ, Humphris, JL, Mead, RS, Nagrial, AM, Pajic, M, Pettit, J, Pinese, M, Rooman, I, Wu, J, Tao, J, DiPietro, R, Watson, C, Steinmann, AM, Lee, H, Wong, R, Pinho, AV, Giry-Laterrière, M, Daly, RJ, Musgrove, EA, Sutherland, RL, Grimmond, SM, Waddell, N, Kassahn, KS, Miller, DK, Wilson, PJ, Patch, AM, Song, S, Harliwong, I, Idrisoglu, S, Nourbakhsh, E, Manning, S, Wani, S, Gongora, MM, Anderson, ML, Holmes, O, Leonard, CR, Taylor, DF, Wood, S, Xu, CW, Nones, K, Fink, JL, Christ, AN, Bruxner, TJ, Cloonan, N, Newell, FS, Pearson, JV, Quinn, MC, Nagaraj, SH, Kazakoff, SH, Waddell, NM, Krisnan, K, Quek, K, Wood, DL, Samra, JS, Gill, AJ, Pavlakis, N, Guminski, AD, Toon, CW, Asghari, R, Merrett, ND & et al 2020, 'HNF4A and GATA6 loss reveals therapeutically actionable subtypes in pancreatic cancer', Cell Reports, vol. 31, no. 6, 107625. https://doi.org/10.1016/j.celrep.2020.107625

TY - JOUR

T1 - HNF4A and GATA6 loss reveals therapeutically actionable subtypes in pancreatic cancer

AU - Brunton, Holly

AU - Caligiuri, Giuseppina

AU - Cunningham, Richard

AU - Upstill-Goddard, Rosie

AU - Bailey, Ulla-Maja

AU - Garner, Ian M.

AU - Nourse, Craig

AU - Dreyer, Stephan

AU - Jones, Marc

AU - Moran-Jones, Kim

AU - Wright, Derek W.

AU - Paulus-Hock, Viola

AU - Nixon, Colin

AU - Thomson, Gemma

AU - Jamieson, Nigel B.

AU - McGregor, Grant A.

AU - Evers, Lisa

AU - McKay, Colin J.

AU - Gulati, Aditi

AU - Brough, Rachel

AU - Bajrami, Ilirjana

AU - Pettitt, Stephen J.

AU - Dziubinski, Michele L.

AU - Barry, Simon T.

AU - Grützmann, Robert

AU - Brown, Robert

AU - Curry, Edward

AU - Allison, Sarah

AU - Biankin, Andrew V.

AU - Chang, David K.

AU - Cook, Susanna L.

AU - Grimwood, Paul

AU - Kelly, Shane

AU - Marshall, John F.

AU - McDade, Brian

AU - McElroy, Daniel

AU - Ramsay, Donna

AU - Rebus, Selma

AU - Hair, Jane

AU - Westwood, Paul

AU - Williams, Nicola

AU - Duthie, Fraser R.

AU - Johns, Amber L.

AU - Mawson, Amanda

AU - Scarlett, Christopher J.

AU - Brancato, Mary Anne L.

AU - Rowe, Sarah J.

AU - Simpson, Skye H.

AU - Martyn-Smith, Mona

AU - Thomas, Michelle T.

AU - Chantrill, Lorraine A.

AU - Chin, Venessa T.

AU - Chou, Angela S.

AU - Cowley, Mark J.

AU - Humphris, Jeremy L.

AU - Mead, Ronald S.

AU - Nagrial, Adnan M.

AU - Pajic, Marina

AU - Pettit, Jessica

AU - Pinese, Mark

AU - Rooman, Ilse

AU - Wu, Jianmin

AU - Tao, Jiang

AU - DiPietro, Renee

AU - Watson, Clare

AU - Steinmann, Angela M.

AU - Lee, Hongching

AU - Wong, Rachel

AU - Pinho, Andreia V.

AU - Giry-Laterrière, Marc

AU - Daly, Roger J.

AU - Musgrove, Elizabeth A.

AU - Sutherland, Robert L.

AU - Grimmond, Sean M.

AU - Waddell, Nicola

AU - Kassahn, Karin S.

AU - Miller, David K.

AU - Wilson, Peter J.

AU - Patch, Ann Marie

AU - Song, Sarah

AU - Harliwong, Ivon

AU - Idrisoglu, Senel

AU - Nourbakhsh, Ehsan

AU - Manning, Suzanne

AU - Wani, Shivangi

AU - Gongora, Milena M.

AU - Anderson, Matthew L.

AU - Holmes, Oliver

AU - Leonard, Conrad R.

AU - Taylor, Darrin F.

AU - Wood, Scott

AU - Xu, Christina W.

AU - Nones, Kátia

AU - Fink, J. Lynn

AU - Christ, Angelika N.

AU - Bruxner, Timothy J.

AU - Cloonan, Nicole

AU - Newell, Felicity S.

AU - Pearson, John V.

AU - Quinn, Michael C.

AU - Nagaraj, Shivashankar H.

AU - Kazakoff, Stephen H.

AU - Waddell, Nick M.

AU - Krisnan, Keerthana

AU - Quek, Kelly

AU - Wood, David L.

AU - Samra, Jaswinder S.

AU - Gill, Anthony J.

AU - Pavlakis, Nick

AU - Guminski, Alexander D.

AU - Toon, Christopher W.

AU - Asghari, Ray

AU - Merrett, Neil D.

AU - et al, null

PY - 2020

Y1 - 2020

N2 - Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages 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 lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3b) a key regulator of glycolysis. Pharmacological inhibition of GSK3b results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3b inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC.

AB - Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages 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 lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3b) a key regulator of glycolysis. Pharmacological inhibition of GSK3b results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3b inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC.

KW - cancer

KW - pancreas

KW - pancreatic acinar cells

KW - pancreatic duct

UR - http://hdl.handle.net/1959.7/uws:57859

U2 - 10.1016/j.celrep.2020.107625

DO - 10.1016/j.celrep.2020.107625

M3 - Article

SN - 2211-1247

VL - 31

JO - Cell Reports

JF - Cell Reports

IS - 6

M1 - 107625

ER -

HNF4A and GATA6 loss reveals therapeutically actionable subtypes in pancreatic cancer

Abstract

Open Access - Access Right Statement

Keywords

UN SDGs

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