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HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer

Brunton H, Caligiuri G, Cunningham R, Upstill-Goddard R, Bailey UM, 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, Cooke SL, Grimwood P, Kelly S, Marshall J, McDade B, McElroy D, Ramsay D, Rebus S, Hair J, Westwood P, Williams N, Duthie F, Johns AL, Mawson A, Scarlett CJ, Brancato MAL, Rowe SJ, Simpson SH, Martyn-Smith M, Thomas MT, Chantrill LA, Chin VT, Chou A, 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 A, Lee HC, Wong R, Pinho AV, Giry-Laterriere 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 M, Anderson M, Holmes O, Leonard C, Taylor D, Wood S, Xu C, Nones K, Fink JL, Christ A, Bruxner T, Cloonan N, Newell F, Pearson JV, Quinn M, Nagaraj S, Kazakoff S, Waddell N, Krisnan K, Quek K, Wood D, Samra JS, Gill AJ, Pavlakis N, Guminski A, Toon C, Asghari R, Merrett ND, Pavey D, Das A, Cosman PH, Ismail K, O'Connnor C, Lam VW, McLeod D, Pleass HC, Richardson A, James V, Kench JG, Cooper CL, Joseph D, Sandroussi C, Crawford M, Gallagher J, Texler M, Forest C, Laycock A, Epari KP, Ballal M, Fletcher DR, Mukhedkar S, Spry NA, DeBoer B, Chai M, Zeps N, Beilin M, Feeney K, Nguyen NQ, Ruszkiewicz AR, Worthley C, Tan CP, Debrencini T, Chen J, Brooke-Smith ME, Papangelis V, Tang H, Barbour AP, Clouston AD, Martin P, O'Rourke TJ, Chiang A, Fawcett JW, Slater K, Yeung S, Hatzifotis M, Hodgkinson P, Christophi C, Nikfarjam M, Mountain A, Eshleman JR, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Hodgin M, Scarpa A, Lawlor RT, Beghelli S, Corbo V, Scardoni M, Bassi C, Tempero MA, Graham JS, Petersen GM, Shanks E, Ashworth A, Crawford HC, Simeone DM, Froeling FE, Lord CJ, Mukhopadhyay D, Pilarsky C, Grimmond SE, Morton JP, Sansom OJ, Bailey PJ (2020)

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Publication Type: Journal article

Publication year: 2020

Journal

Book Volume: 31

Article Number: 107625

Journal Issue: 6

DOI: 10.1016/j.celrep.2020.107625

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. Brunton et al. demonstrate that differential chromatin accessibility can predict responsiveness and tolerance to GSK3β inhibitors in the squamous subtype of PDAC. This study provides an important proof of concept that chromatin accessibility can be used to identify additional PDAC subgroups with potential therapeutic utility.

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APA:

Brunton, H., Caligiuri, G., Cunningham, R., Upstill-Goddard, R., Bailey, U.M., Garner, I.M.,... Bailey, P.J. (2020). HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer. Cell Reports, 31(6). https://doi.org/10.1016/j.celrep.2020.107625

MLA:

Brunton, Holly, et al. "HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer." Cell Reports 31.6 (2020).

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