HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer

Glasgow Precision Oncology Laboratory; 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; Marina Pajic; Elizabeth A Musgrove; Gloria M Petersen; Emma Shanks; Alan Ashworth; Howard C Crawford; Diane M Simeone; Fieke E M Froeling; Christopher J Lord; Debabrata Mukhopadhyay; Christian Pilarsky; Sean E Grimmond; Jennifer P Morton; Owen J Sansom; David K Chang; Peter J Bailey; Andrew V Biankin

doi:10.1016/j.celrep.2020.107625

HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer

Glasgow Precision Oncology Laboratory, 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 GulatiRachel Brough, Ilirjana Bajrami, Stephen J Pettitt, Michele L Dziubinski, Simon T Barry, Robert Grützmann, Robert Brown, Edward Curry, Marina Pajic, Elizabeth A Musgrove, Gloria M Petersen, Emma Shanks, Alan Ashworth, Howard C Crawford, Diane M Simeone, Fieke E M Froeling, Christopher J Lord, Debabrata Mukhopadhyay, Christian Pilarsky, Sean E Grimmond, Jennifer P Morton, Owen J Sansom, David K Chang, Peter J Bailey, Andrew V Biankin

Basic (bio-) Medical Sciences

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

78 Citations (Scopus)

94 Downloads (Pure)

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 (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β 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 GSK3β 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	28
Journal	Cell Reports
Volume	31
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2020.107625
Publication status	Published - 12 May 2020

Bibliographical note

Keywords

GATA6
GSK3B
HNF4A
PDAC subtypes
chromatin landscapes
intronic and distal promoters
metabolic targeting
therapeutic tolerance

Access to Document

10.1016/j.celrep.2020.107625Licence: CC BY

brunton 2020Final published version, 4.38 MBLicence: CC BY

Cite this

Glasgow Precision Oncology Laboratory, 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., ... Biankin, A. V. (2020). HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer. Cell Reports, 31(6), [107625]. https://doi.org/10.1016/j.celrep.2020.107625

Glasgow Precision Oncology Laboratory ; Brunton, Holly ; Caligiuri, Giuseppina ; Cunningham, Richard ; Upstill-Goddard, Rosie ; Bailey, Ulla-Maja ; Garner, Ian M ; Nourse, Craig ; Dreyer, Stephan ; Jones, Marc ; Moran-Jones, Kim ; Wright, Derek W ; Paulus-Hock, Viola ; Nixon, Colin ; Thomson, Gemma ; Jamieson, Nigel B ; McGregor, Grant A ; Evers, Lisa ; McKay, Colin J ; Gulati, Aditi ; Brough, Rachel ; Bajrami, Ilirjana ; Pettitt, Stephen J ; Dziubinski, Michele L ; Barry, Simon T ; Grützmann, Robert ; Brown, Robert ; Curry, Edward ; Pajic, Marina ; Musgrove, Elizabeth A ; Petersen, Gloria M ; Shanks, Emma ; Ashworth, Alan ; Crawford, Howard C ; Simeone, Diane M ; Froeling, Fieke E M ; Lord, Christopher J ; Mukhopadhyay, Debabrata ; Pilarsky, Christian ; Grimmond, Sean E ; Morton, Jennifer P ; Sansom, Owen J ; Chang, David K ; Bailey, Peter J ; Biankin, Andrew V. / HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer. In: Cell Reports. 2020 ; Vol. 31, No. 6.

@article{341dd99037744d07a927f034929cde3f,

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 (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β 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 GSK3β 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 = "GATA6, GSK3B, HNF4A, PDAC subtypes, chromatin landscapes, intronic and distal promoters, metabolic targeting, therapeutic tolerance",

author = "{Glasgow Precision Oncology Laboratory} and 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 Marina Pajic and Musgrove, {Elizabeth A} and Petersen, {Gloria M} and Emma Shanks and Alan Ashworth and Crawford, {Howard C} and Simeone, {Diane M} and Froeling, {Fieke E M} and Lord, {Christopher J} and Debabrata Mukhopadhyay and Christian Pilarsky and Grimmond, {Sean E} and Morton, {Jennifer P} and Sansom, {Owen J} and Chang, {David K} and Bailey, {Peter J} and Biankin, {Andrew V} and Ilse Rooman",

year = "2020",

month = may,

day = "12",

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

language = "English",

volume = "31",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "6",

}

Glasgow Precision Oncology Laboratory, 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, Pajic, M, Musgrove, EA, Petersen, GM, Shanks, E, Ashworth, A, Crawford, HC, Simeone, DM, Froeling, FEM, Lord, CJ, Mukhopadhyay, D, Pilarsky, C, Grimmond, SE, Morton, JP, Sansom, OJ, Chang, DK, Bailey, PJ & Biankin, AV 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

HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer. / Glasgow Precision Oncology Laboratory; Brunton, Holly; Caligiuri, Giuseppina; Cunningham, Richard; Upstill-Goddard, Rosie; Bailey, Ulla-Maja; Garner, Ian M; Nourse, Craig; Dreyer, Stephan; Jones, Marc; Moran-Jones, Kim; Wright, Derek W; Paulus-Hock, Viola; Nixon, Colin; Thomson, Gemma; Jamieson, Nigel B; McGregor, Grant A; Evers, Lisa; McKay, Colin J; Gulati, Aditi; Brough, Rachel; Bajrami, Ilirjana; Pettitt, Stephen J; Dziubinski, Michele L; Barry, Simon T; Grützmann, Robert; Brown, Robert; Curry, Edward; Pajic, Marina; Musgrove, Elizabeth A; Petersen, Gloria M; Shanks, Emma; Ashworth, Alan; Crawford, Howard C; Simeone, Diane M; Froeling, Fieke E M; Lord, Christopher J; Mukhopadhyay, Debabrata; Pilarsky, Christian; Grimmond, Sean E; Morton, Jennifer P; Sansom, Owen J; Chang, David K; Bailey, Peter J; Biankin, Andrew V.

In: Cell Reports, Vol. 31, No. 6, 107625, 12.05.2020.

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

TY - JOUR

T1 - HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer

AU - Glasgow Precision Oncology Laboratory

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 - Pajic, Marina

AU - Musgrove, Elizabeth A

AU - Petersen, Gloria M

AU - Shanks, Emma

AU - Ashworth, Alan

AU - Crawford, Howard C

AU - Simeone, Diane M

AU - Froeling, Fieke E M

AU - Lord, Christopher J

AU - Mukhopadhyay, Debabrata

AU - Pilarsky, Christian

AU - Grimmond, Sean E

AU - Morton, Jennifer P

AU - Sansom, Owen J

AU - Chang, David K

AU - Bailey, Peter J

AU - Biankin, Andrew V

AU - Rooman, Ilse

PY - 2020/5/12

Y1 - 2020/5/12

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 (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β 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 GSK3β 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 (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β 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 GSK3β 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 - GATA6

KW - GSK3B

KW - HNF4A

KW - PDAC subtypes

KW - chromatin landscapes

KW - intronic and distal promoters

KW - metabolic targeting

KW - therapeutic tolerance

UR - http://www.scopus.com/inward/record.url?scp=85084363031&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2020.107625

DO - 10.1016/j.celrep.2020.107625

M3 - Article

C2 - 32402285

VL - 31

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 6

M1 - 107625

ER -

HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Fingerprint

FWOODYS12: De-convolution of tumour biology in the post-genomic era: focus on pancreatic cancer

Cite this

HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Fingerprint

Projects

FWOODYS12: De-convolution of tumour biology in the post-genomic era: focus on pancreatic cancer

Cite this