GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer
Paola Martinelli,Enrique Carrillo-de Santa Pau,Trevor Cox,Bruno Sainz,Nelson Dusetti,William Greenhalf,Lorenzo Rinaldi,Eithne Costello,Paula Ghaneh,Núria Malats,Markus W. Büchler,Marina Pajic,Andrew V. Biankin,Juan L. Iovanna,John P. Neoptolemos,Francisco X. Real +15 more
Reads0
Chats0
TLDR
The role of GATA factors in cancer has gained increasing attention recently, but the function of Gata6 in pancreatic ductal adenocarcinoma (PDAC) is controversial.Abstract:
Background and aims The role of GATA factors in cancer has gained increasing attention recently, but the function of GATA6 in pancreatic ductal adenocarcinoma (PDAC) is controversial. GATA6 is amplified in a subset of tumours and was proposed to be oncogenic, but high GATA6 levels are found in well-differentiated tumours and are associated with better patient outcome. By contrast, a tumour-suppressive function of GATA6 was demonstrated using genetic mouse models. We aimed at clarifying GATA6 function in PDAC. Design We combined GATA6 silencing and overexpression in PDAC cell lines with GATA6 ChIP-Seq and RNA-Seq data, in order to understand the mechanism of GATA6 functions. We then confirmed some of our observations in primary patient samples, some of which were included in the ESPAC-3 randomised clinical trial for adjuvant therapy. Results GATA6 inhibits the epithelial–mesenchymal transition (EMT) in vitro and cell dissemination in vivo. GATA6 has a unique proepithelial and antimesenchymal function, and its transcriptional regulation is direct and implies, indirectly, the regulation of other transcription factors involved in EMT. GATA6 is lost in tumours, in association with altered differentiation and the acquisition of a basal-like molecular phenotype, consistent with an epithelial-to-epithelial (ET 2 ) transition. Patients with basal-like GATA6 low tumours have a shorter survival and have a distinctly poor response to adjuvant 5-fluorouracil (5-FU)/leucovorin. However, modulation of GATA6 expression in cultured cells does not directly regulate response to 5-FU. Conclusions We provide mechanistic insight into GATA6 tumour-suppressive function, its role as a regulator of canonical epithelial differentiation, and propose that loss of GATA6 expression is both prognostic and predictive of response to adjuvant therapy.read more
Citations
More filters
Journal ArticleDOI
Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma
Benjamin J. Raphael,Ralph H. Hruban,Andrew J. Aguirre,Richard A. Moffitt,Jen Jen Yeh,Chip Stewart,A. Gordon Robertson,Andrew D. Cherniack,Manaswi Gupta,Gad Getz,Stacey Gabriel,Matthew Meyerson,Carrie Cibulskis,Suzanne S. Fei,Toshinori Hinoue,Hui Shen,Peter W. Laird,Shiyun Ling,Yiling Lu,Gordon B. Mills,Rehan Akbani,Phillipe Loher,Eric Londin,Isidore Rigoutsos,Aristeidis G. Telonis,Ewan A. Gibb,Anna Goldenberg,Aziz M. Mezlini,Katherine A. Hoadley,Eric A. Collisson,Eric S. Lander,Bradley A. Murray,Julian M. Hess,Mara Rosenberg,Louis Bergelson,Hailei Zhang,Juok Cho,Grace Tiao,Jaegil Kim,Dimitri Livitz,Ignaty Leshchiner,Brendan Reardon,Eliezer M. Van Allen,Atanas Kamburov,Rameen Beroukhim,Gordon Saksena,Steven E. Schumacher,Michael S. Noble,David I. Heiman,Nils Gehlenborg,Michael S. Lawrence,Volkan Adsay,Gloria M. Petersen,David S. Klimstra,Nabeel Bardeesy,Mark D.M. Leiserson,Reanne Bowlby,Katayoon Kasaian,Inanc Birol,Karen Mungall,Sara Sadeghi,John N. Weinstein,Paul T. Spellman,Yuexin Liu,Laufey T. Amundadottir,Joel E. Tepper,Aatur D. Singhi,Rajiv Dhir,Drwiega Paul,Thomas C. Smyrk,Lizhi Zhang,Paula Kim,Jay Bowen,Jessica Frick,Julie M. Gastier-Foster,Mark Gerken,Kevin Lau,Kristen M. Leraas,Tara M. Lichtenberg,Nilsa C. Ramirez,Jeremy Renkel,Mark E. Sherman,Lisa Wise,Peggy Yena,Erik Zmuda,Juliann Shih,Adrian Ally,Miruna Balasundaram,Rebecca Carlsen,Andy Chu,Eric Chuah,Amanda Clarke,Noreen Dhalla,Robert A. Holt,Steven J.M. Jones,Darlene Lee,Yussanne Ma,Marco A. Marra,Michael Mayo,Richard A. Moore,Andrew J. Mungall,Jacqueline E. Schein,Payal Sipahimalani,Angela Tam,Nina Thiessen,Kane Tse,Tina Wong,Denise Brooks,J. Todd Auman,Saianand Balu,Tom Bodenheimer,D. Neil Hayes,Alan P. Hoyle,Stuart R. Jefferys,Corbin D. Jones,Shaowu Meng,Piotr A. Mieczkowski,Lisle E. Mose,Charles M. Perou,Amy H. Perou,Jeffrey Roach,Yan Shi,Janae V. Simons,Tara Skelly,Matthew G. Soloway,Donghui Tan,Umadevi Veluvolu,Joel S. Parker,Matthew D. Wilkerson,Anil Korkut,Yasin Senbabaoglu,Patrick Burch,Robert R. McWilliams,Kari G. Chaffee,Ann L. Oberg,Wei Zhang,Marie-Claude Gingras,David A. Wheeler,Liu Xi,Monique Albert,John M. S. Bartlett,Harman Sekhon,Yeager Stephen,Zaren Howard,Miller Judy,Anne Breggia,Rachna T. Shroff,Sudha Chudamani,Jia Liu,Laxmi Lolla,Rashi Naresh,Todd Pihl,Qiang Sun,Yunhu Wan,Ye Wu,Smith Jennifer,Kevin Roggin,Karl-Friedrich Becker,Madhusmita Behera,Joseph J. Bennett,Lori Boice,Eric J. Burks,Carlos Gilberto Carlotti Junior,John Chabot,Daniela Pretti da Cunha Tirapelli,Jose Sebastião dos Santos,Michael Dubina,Jennifer M. Eschbacher,Mei Huang,Lori Huelsenbeck-Dill,Roger Jenkins,Alexey Karpov,Rafael Kemp,Vladimir Lyadov,Shishir K. Maithel,Georgy Manikhas,Eric Montgomery,Houtan Noushmehr,Adeboye O. Osunkoya,Taofeek K. Owonikoko,Oxana Paklina,Olga Potapova,Suresh S. Ramalingam,W. Kimryn Rathmell,Kimberly M. Rieger-Christ,Charles Saller,Galiya Setdikova,Alexey Shabunin,Gabriel Sica,Tao Su,Travis Sullivan,Pat Swanson,Katherine Tarvin,Michael Tavobilov,Leigh B. Thorne,Stefan Urbanski,Olga Voronina,Timothy C. Wang,Daniel Crain,Erin Curley,Johanna Gardner,David Mallery,Scott J. Morris,Joseph Paulauskis,Robert Penny,Candace Shelton,Troy Shelton,Klaus-Peter Janssen,Oliver F. Bathe,Nathan Bahary,Julia Slotta-Huspenina,Amber L. Johns,Hanina Hibshoosh,Rosa F. Hwang,Antonia R. Sepulveda,Amie Radenbaugh,Stephen B. Baylin,Mario Berrios,Moiz S. Bootwalla,Andrea Holbrook,Phillip H. Lai,Dennis T. Maglinte,Swapna Mahurkar,Timothy J. Triche,David Van Den Berg,Daniel J. Weisenberger,Lynda Chin,Raju Kucherlapati,Melanie H. Kucherlapati,Angeliki Pantazi,Peter J. Park,Doug Voet,Pei Lin,Scott Frazer,Timothy Defreitas,Sam Meier,Sun Young Kwon,Yong Hoon Kim,Sang Jae Park,Sung Sik Han,Seong Hoon Kim,Hark Kyun Kim,Emma E. Furth,Margaret A. Tempero,Chris Sander,Andrew V. Biankin,David K. Chang,Peter Bailey,Anthony J. Gill,James G. Kench,Sean M. Grimmond,Russell Postier,Rosemary E. Zuna,Hugues Sicotte,John A. Demchok,Martin L. Ferguson,Carolyn M. Hutter,Kenna R. Mills Shaw,Margi Sheth,Heidi J. Sofia,Roy Tarnuzzer,Zhining Wang,Liming Yang,Jiashan Zhang,Ina Felau,Jean C. Zenklusen +265 more
TL;DR: An integrated multi-platform analysis of 150 pancreatic ductal adenocarcinoma specimens reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.
Journal ArticleDOI
The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer
Angela M. Krebs,Julia Mitschke,María Lasierra Losada,Otto Schmalhofer,Melanie Boerries,Melanie Boerries,Hauke Busch,Hauke Busch,Martin Boettcher,Dimitrios Mougiakakos,Wilfried Reichardt,Wilfried Reichardt,Peter Bronsert,Peter Bronsert,Valerie G. Brunton,Christian Pilarsky,Thomas Winkler,Simone Brabletz,Marc P. Stemmler,Thomas Brabletz +19 more
TL;DR: It is shown that different EMT-TFs have complementary subfunctions in driving pancreatic tumour metastasis, and that Depletion of Zeb1 suppresses stemness, colonization capacity and in particular phenotypic/metabolic plasticity of tumour cells, probably causing the observed in vivo effects.
Journal ArticleDOI
Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial
Kyaw L. Aung,Sandra Fischer,Sandra Fischer,Robert E. Denroche,Gun-Ho Jang,Anna Dodd,Sean Creighton,Bernadette Southwood,Sheng-Ben Liang,Dianne Chadwick,Amy Zhang,Grainne M. O'Kane,Hamzeh Albaba,Shari Moura,Robert C. Grant,Jessica Miller,Faridah Mbabaali,Danielle Pasternack,Ilinca Lungu,John M. S. Bartlett,Sangeet Ghai,Mathieu Lemire,Spring Holter,Ashton A. Connor,Richard A. Moffitt,Richard A. Moffitt,Jen Jen Yeh,Lee Timms,Paul M. Krzyzanowski,Neesha C. Dhani,David W. Hedley,Faiyaz Notta,Julie M. Wilson,Malcolm J. Moore,Steven Gallinger,Jennifer J. Knox +35 more
TL;DR: Prospective genomic profiling of advanced PDAC is feasible, and early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes.
Journal ArticleDOI
lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/β-catenin signaling
Yuanyuan Lu,Xiaodi Zhao,Xiaodi Zhao,Qi Liu,Cunxi Li,Ramona Graves-Deal,Zheng Cao,Bhuminder Singh,Jeffrey L. Franklin,Jing Wang,Huaying Hu,Tian-Ying Wei,Mingli Yang,Timothy J. Yeatman,Ethan Lee,Kenyi Saito-Diaz,Scott Hinger,James G. Patton,Christine H. Chung,Stephan Emmrich,Jan-Henning Klusmann,Daiming Fan,Robert J. Coffey,Robert J. Coffey +23 more
TL;DR: These findings identify a clinically actionable, epigenetic cause of cetuximab resistance, and describe a double-negative feedback loop between MIR100HG and the transcription factor GATA6, whereby Gata6 represses MIR 100HG, but this repression is relieved by miR-125b targeting of GATA 6.
Journal ArticleDOI
GATA6 Expression Distinguishes Classical and Basal-like Subtypes in Advanced Pancreatic Cancer
Grainne M. O'Kane,Barbara Grünwald,Barbara Grünwald,Gun-Ho Jang,Mehdi Masoomian,Sarah Picardo,Robert C. Grant,Robert C. Grant,Robert E. Denroche,Amy Zhang,Yifan Wang,Yifan Wang,Bernard Lam,Paul M. Krzyzanowski,Illinca M. Lungu,John M. S. Bartlett,Melanie Peralta,Foram Vyas,Rama Khokha,James Joseph Biagi,Dianne Chadwick,Stephanie Ramotar,Shawn Hutchinson,Anna Dodd,Julie M. Wilson,Faiyaz Notta,Faiyaz Notta,George Zogopoulos,George Zogopoulos,Steven Gallinger,Jennifer J. Knox,Sandra Fischer +31 more
TL;DR: The basal-like subtype is chemoresistant and can be distinguished from classical PDAC by GATA6 expression, which was prognostic and predicted the subtypes with sensitivity and specificity.
References
More filters
Journal ArticleDOI
Specific GATA factors act as conserved inducers of an endodermal-EMT.
TL;DR: A set of GATA factors are identified as a conserved alternative trigger to repress epithelial characteristics and confer migratory capabilities on epithelial cells in development and pathogenesis.
Journal ArticleDOI
Gata6 is required for complete acinar differentiation and maintenance of the exocrine pancreas in adult mice
Paola Martinelli,Marta Cañamero,Natalia del Pozo,Francesc Madriles,Agustín G. Zapata,Francisco X. Real +5 more
TL;DR: The data show that Gata6 is required for the complete differentiation of acinar cells through multiple transcriptional regulatory mechanisms, which suggests that GATA6 alterations may contribute to diseases of the human adult exocrine pancreas.
Journal ArticleDOI
The acinar regulator Gata6 suppresses KrasG12V-driven pancreatic tumorigenesis in mice
Paola Martinelli,Francesc Madriles,Marta Cañamero,Enrique Carrillo-de Santa Pau,Natalia del Pozo,Carmen Guerra,Francisco X. Real +6 more
TL;DR: It is proposed that, in the pancreas, Gata6 acts as a tumour suppressor by enforcing acinar cell differentiation, by directly and indirectly repressing ectopic differentiation programmes, and by regulating crucial cancer-related gene expression pathways.
Journal ArticleDOI
Frequent genomic copy number gain and overexpression of GATA-6 in pancreatic carcinoma.
TL;DR: Using Representational Oligonucleotide Microarray Analysis (ROMA) to identify copy number changes in pancreatic cancer xenografts, GATA-6 mRNA overexpression corresponded to robust nuclear protein expression in cancer cell lines and resected tissues consistent with its role as a transcription factor.
Journal ArticleDOI
A Migration Signature and Plasma Biomarker Panel for Pancreatic Adenocarcinoma
Seetharaman Balasenthil,Nanyue Chen,Steven T. Lott,Jinyun Chen,Jennifer Carter,William E. Grizzle,Marsha L. Frazier,Subrata Sen,Ann M. Killary +8 more
TL;DR: A novel 3p pathway–associated migration signature and plasma biomarker panel that has utility for discrimination of pancreatic cancer from normal controls and promise for clinical application is identified.
Related Papers (5)
Genomic analyses identify molecular subtypes of pancreatic cancer
Peter Bailey,David K. Chang,Katia Nones,Katia Nones,Amber L. Johns,Ann-Marie Patch,Ann-Marie Patch,Marie-Claude Gingras,David Miller,David Miller,Angelika N. Christ,Timothy J. C. Bruxner,Michael C.J. Quinn,Michael C.J. Quinn,Craig Nourse,Craig Nourse,Murtaugh Lc,Ivon Harliwong,Senel Idrisoglu,Suzanne Manning,Ehsan Nourbakhsh,Shivangi Wani,Shivangi Wani,J. Lynn Fink,Oliver Holmes,Oliver Holmes,Chin,Matthew J. Anderson,Stephen H. Kazakoff,Stephen H. Kazakoff,Conrad Leonard,Conrad Leonard,Felicity Newell,Nicola Waddell,Scott Wood,Scott Wood,Qinying Xu,Qinying Xu,Peter J. Wilson,Nicole Cloonan,Nicole Cloonan,Karin S. Kassahn,Karin S. Kassahn,Karin S. Kassahn,Darrin Taylor,Kelly Quek,Alan J. Robertson,Lorena Pantano,Laura Mincarelli,Luis Navarro Sanchez,Lisa Evers,Jianmin Wu,Mark Pinese,Mark J. Cowley,Jones,Jones,Emily K. Colvin,Adnan Nagrial,Emily S. Humphrey,Lorraine A. Chantrill,Lorraine A. Chantrill,Amanda Mawson,Jeremy L. Humphris,Angela Chou,Angela Chou,Marina Pajic,Marina Pajic,Christopher J. Scarlett,Christopher J. Scarlett,Andreia V. Pinho,Marc Giry-Laterriere,Ilse Rooman,Jaswinder S. Samra,James G. Kench,James G. Kench,James G. Kench,Jessica A. Lovell,Neil D. Merrett,Christopher W. Toon,Krishna Epari,Nam Q. Nguyen,Andrew Barbour,Nikolajs Zeps,Kim Moran-Jones,Nigel B. Jamieson,Janet Graham,Janet Graham,Fraser Duthie,Karin A. Oien,Karin A. Oien,Hair J,Robert Grützmann,Anirban Maitra,Christine A. Iacobuzio-Donahue,Christopher L. Wolfgang,Richard A. Morgan,Rita T. Lawlor,Corbo,Claudio Bassi,Borislav Rusev,Paola Capelli,Roberto Salvia,Giampaolo Tortora,Debabrata Mukhopadhyay,Gloria M. Petersen,Munzy Dm,William E. Fisher,Saadia A. Karim,Eshleman,Ralph H. Hruban,Christian Pilarsky,Jennifer P. Morton,Owen J. Sansom,Aldo Scarpa,Elizabeth A. Musgrove,Ulla-Maja Bailey,Oliver Hofmann,Oliver Hofmann,R. L. Sutherland,David A. Wheeler,Anthony J. Gill,Anthony J. Gill,Richard A. Gibbs,John V. Pearson,John V. Pearson,Andrew V. Biankin,Sean M. Grimmond,Sean M. Grimmond,Sean M. Grimmond +128 more
Whole genomes redefine the mutational landscape of pancreatic cancer.
Nicola Waddell,Marina Pajic,Ann-Marie Patch,David K. Chang,Karin S. Kassahn,Peter Bailey,Amber L. Johns,David Miller,Katia Nones,Kelly Quek,Michael C.J. Quinn,Alan J. Robertson,Muhammad Zaki Hidayatullah Fadlullah,Timothy J. C. Bruxner,Angelika N. Christ,Ivon Harliwong,Senel Idrisoglu,Suzanne Manning,Craig Nourse,Ehsan Nourbakhsh,Shivangi Wani,Peter J. Wilson,Emma Markham,Nicole Cloonan,Matthew J. Anderson,J. Lynn Fink,Oliver Holmes,Stephen H. Kazakoff,Conrad Leonard,Felicity Newell,Barsha Poudel,Sarah Song,Darrin Taylor,Nick Waddell,Scott Wood,Qinying Xu,Jianmin Wu,Mark Pinese,Mark J. Cowley,Hong C. Lee,Marc D. Jones,Adnan Nagrial,Jeremy L. Humphris,Lorraine A. Chantrill,Venessa T. Chin,Angela Steinmann,Amanda Mawson,Emily S. Humphrey,Emily K. Colvin,Angela Chou,Christopher J. Scarlett,Andreia V. Pinho,Marc Giry-Laterriere,Ilse Rooman,Jaswinder S. Samra,James G. Kench,Jessica A. Pettitt,Neil D. Merrett,Christopher W. Toon,Krishna Epari,Nam Q. Nguyen,Andrew Barbour,Nikolajs Zeps,Nigel B. Jamieson,Janet Graham,Simone P. Niclou,Rolf Bjerkvig,Robert Grützmann,Daniela Aust,Ralph H. Hruban,Anirban Maitra,Christine A. Iacobuzio-Donahue,Christopher L. Wolfgang,Richard A. Morgan,Rita T. Lawlor,Vincenzo Corbo,Claudio Bassi,Massimo Falconi,Giuseppe Zamboni,Giampaolo Tortora,Margaret A. Tempero,Anthony J. Gill,James R. Eshleman,Christian Pilarsky,Aldo Scarpa,Elizabeth A. Musgrove,John V. Pearson,Andrew V. Biankin,Sean M. Grimmond +88 more
FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer
Thierry Conroy,Françoise Desseigne,Marc Ychou,Olivier Bouché,Rosine Guimbaud,Yves Becouarn,Antoine Adenis,Jean-Luc Raoul,Sophie Gourgou-Bourgade,Jaafar Bennouna,Jean-Baptiste Bachet,Faiza Khemissa-Akouz,Denis Péré-Vergé,Catherine Delbaldo,Eric Assenat,Bruno Chauffert,C. Montoto-Grillot,Michel Ducreux +17 more
Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine
Daniel D. Von Hoff,Thomas J. Ervin,Francis P. Arena,E. Gabriela Chiorean,Jeffrey R. Infante,Malcolm J. Moore,Thomas E. Seay,Sergei Tjulandin,Wen Wee Ma,Mansoor N. Saleh,Marion Harris,Michele Reni,Scot Dowden,Daniel A. Laheru,Nathan Bahary,Ramesh K. Ramanathan,Josep Tabernero,Manuel Hidalgo,David Goldstein,Eric Van Cutsem,Xinyu Wei,Jose Iglesias,Markus F. Renschler +22 more