Human Pancreatic Tumor Organoids Reveal Loss of Stem Cell Niche Factor Dependence during Disease Progression

被引：520

作者：

Seino, Takashi ^{[1
]}

Kawasaki, Shintaro ^{[1
]}

Shimokawa, Mariko ^{[1
]}

Tamagawa, Hiroki ^{[1
]}

Toshimitsu, Kohta ^{[1
]}

Fujii, Masayuki ^{[1
]}

Ohta, Yuki ^{[1
]}

Matano, Mami ^{[1
]}

Nanki, Kosaku ^{[1
]}

Kawasaki, Kenta ^{[1
]}

Takahashi, Sirirat ^{[1
]}

Sugimoto, Shinya ^{[1
]}

Iwasaki, Eisuke ^{[1
]}

Takagi, Junichi ^{[3
]}

Itoi, Takao ^{[4
]}

Kitago, Minoru ^{[2
]}

Kitagawa, Yuko ^{[2
]}

Kanai, Takanori ^{[1
]}

Sato, Toshiro ^{[1
]}

机构：

[1] Keio Univ, Sch Med, Dept Gastroenterol, Tokyo 1608582, Japan

[2] Keio Univ, Sch Med, Dept Surg, Tokyo 1608582, Japan

[3] Osaka Univ, Inst Prot Res, Lab Prot Synth & Express, Suita, Osaka 5650871, Japan

[4] Tokyo Med Univ, Dept Gastroenterol, Tokyo 1600023, Japan

来源：

CELL STEM CELL | 2018年 / 22卷 / 03期

基金：

日本学术振兴会;

关键词：

HUMAN INTESTINAL ORGANOIDS; MUTANT K-RAS; DUCTAL ADENOCARCINOMA; IN-VITRO; KNOCK-IN; CANCER; MOUSE; SUBTYPES; SUPPORT; MODELS;

D O I：

10.1016/j.stem.2017.12.009

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Despite recent efforts to dissect the inter-tumor heterogeneity of pancreatic ductal adenocarcinoma (PDAC) by determining prognosis-predictive gene expression signatures for specific subtypes, their functional differences remain elusive. Here, we established a pancreatic tumor organoid library encompassing 39 patient-derived PDACs and identified 3 functional subtypes based on their stem cell niche factor dependencies on Wnt and R-spondin. A Wnt-non-producing subtype required Wnt from cancer-associated fibroblasts, whereas a Wnt-producing subtype autonomously secreted Wnt ligands and an R-spondin-independent subtype grew in the absence of Wnt and R-spondin. Transcriptome analysis of PDAC organoids revealed gene-expression signatures that associated Wnt niche subtypes with GATA6-dependent gene expression subtypes, which were functionally supported by genetic perturbation of GATA6. Furthermore, CRISPR-Cas9-based genome editing of PDAC driver genes (KRAS, CDKN2A, SMAD4, and TP53) demonstrated non-genetic acquisition of Wnt niche independence during pancreas tumorigenesis. Collectively, our results reveal functional heterogeneity of Wnt niche independency in PDAC that is non-genetically formed through tumor progression.

引用

页码：454 / +

页数：20

共 50 条

[1] Pancreatic stellate cells: a starring role in normal and diseased pancreas [J].

Apte, Minoti V. ;

Pirola, Romano C. ;

Wilson, Jeremy S. .

FRONTIERS IN PHYSIOLOGY, 2012, 3

[2] Knock-in of oncogenic Kras does not transform mouse somatic cells but triggers a transcriptional response that classifies human cancers [J].

Arena, Sabrina ;

Isella, Claudio ;

Martini, Miriam ;

de Marco, Ario ;

Medico, Enzo ;

Bardelli, Alberto .

CANCER RESEARCH, 2007, 67 (18) :8468-8476

[3] Genomic analyses identify molecular subtypes of pancreatic cancer [J].

Bailey, Peter ;

Chang, David K. ;

Nones, Katia ;

Johns, Amber L. ;

Patch, Ann-Marie ;

Gingras, Marie-Claude ;

Miller, David K. ;

Christ, Angelika N. ;

Bruxner, Tim J. C. ;

Quinn, Michael C. ;

Nourse, Craig ;

Murtaugh, L. Charles ;

Harliwong, Ivon ;

Idrisoglu, Senel ;

Manning, Suzanne ;

Nourbakhsh, Ehsan ;

Wani, Shivangi ;

Fink, Lynn ;

Holmes, Oliver ;

Chin, Vencssa ;

Anderson, Matthew J. ;

Kazakoff, Stephen ;

Leonard, Conrad ;

Newell, Felicity ;

Waddell, Nick ;

Wood, Scott ;

Xu, Qinying ;

Wilson, Peter J. ;

Cloonan, Nicole ;

Kassahn, Karin S. ;

Taylor, Darrin ;

Quek, Kelly ;

Robertson, Alan ;

Pantano, Lorena ;

Mincarelli, Laura ;

Sanchez, Luis N. ;

Evers, Lisa ;

Wu, Jianmin ;

Pinese, Mark ;

Cowley, Mark J. ;

Jones, Marc D. ;

Colvin, Emily K. ;

Nagrial, Adnan M. ;

Humphrey, Emily S. ;

Chantrill, Lorraine A. ;

Mawson, Amanda ;

Humphris, Jeremy ;

Chou, Angela ;

Pajic, Marina ;

Scarlett, Christopher J. .

NATURE, 2016, 531 (7592) :47-+

[4] Organoid Models of Human and Mouse Ductal Pancreatic Cancer [J].

Boj, Sylvia F. ;

Hwang, Chang-Il ;

Baker, Lindsey A. ;

Chio, Iok In Christine ;

Engle, Dannielle D. ;

Corbo, Vincenzo ;

Jager, Myrthe ;

Ponz-Sarvise, Mariano ;

Tiriac, Herve ;

Spector, Mona S. ;

Gracanin, Ana ;

Oni, Tobiloba ;

Yu, Kenneth H. ;

van Boxtel, Ruben ;

Huch, Meritxell ;

Rivera, Keith D. ;

Wilson, John P. ;

Feigin, Michael E. ;

Oehlund, Daniel ;

Handly-Santana, Abram ;

Ardito-Abraham, Christine M. ;

Ludwig, Michael ;

Elyada, Ela ;

Alagesan, Brinda ;

Biffi, Giulia ;

Yordanov, Georgi N. ;

Delcuze, Bethany ;

Creighton, Brianna ;

Wright, Kevin ;

Park, Youngkyu ;

Morsink, Folkert H. M. ;

Molenaar, I. Quintus ;

Rinkes, Inne H. Borel ;

Cuppen, Edwin ;

Hao, Yuan ;

Jin, Ying ;

Nijman, Isaac J. ;

Iacobuzio-Donahue, Christine ;

Leach, Steven D. ;

Pappin, Darryl J. ;

Hammell, Molly ;

Klimstra, David S. ;

Basturk, Olca ;

Hruban, Ralph H. ;

Offerhaus, George Johan ;

Vries, Robert G. J. ;

Clevers, Hans ;

Tuveson, David A. .

CELL, 2015, 160 (1-2) :324-338

[5]

Brembeck FH, 2003, CANCER RES, V63, P2005

[6] The human and mouse GATA-6 genes utilize two promoters and two initiation codons [J].

Brewer, A ;

Gove, C ;

Davies, A ;

McNulty, C ;

Barrow, D ;

Koutsourakis, M ;

Farzaneh, F ;

Pizzey, J ;

Bomford, A ;

Patient, R .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (53) :38004-38016

[7] Control of Alveolar Differentiation by the Lineage Transcription Factors GATA6 and HOPX Inhibits Lung Adenocarcinoma Metastasis [J].

Cheung, William K. C. ;

Zhao, Minghui ;

Liu, Zongzhi ;

Stevens, Laura E. ;

Cao, Paul D. ;

Fang, Justin E. ;

Westbrook, Thomas F. ;

Nguyen, Don X. .

CANCER CELL, 2013, 23 (06) :725-738

[8] Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy [J].

Collisson, Eric A. ;

Sadanandam, Anguraj ;

Olson, Peter ;

Gibb, William J. ;

Truitt, Morgan ;

Gu, Shenda ;

Cooc, Janine ;

Weinkle, Jennifer ;

Kim, Grace E. ;

Jakkula, Lakshmi ;

Feiler, Heidi S. ;

Ko, Andrew H. ;

Olshen, Adam B. ;

Danenberg, Kathleen L. ;

Tempero, Margaret A. ;

Spellman, Paul T. ;

Hanahan, Douglas ;

Gray, Joe W. .

NATURE MEDICINE, 2011, 17 (04) :500-U140

[9] rCGH: a comprehensive array-based genomic profile platform for precision medicine [J].

Commo, Frederic ;

Guinney, Justin ;

Ferte, Charles ;

Bot, Brian ;

Lefebvre, Celine ;

Soria, Jean-Charles ;

Andre, Fabrice .

BIOINFORMATICS, 2016, 32 (09) :1402-1404

[10] Enhancing zinc-finger-nuclease activity with improved obligate heterodimeric architectures [J].

Doyon, Yannick ;

Vo, Thuy D. ;

Mendel, Matthew C. ;

Greenberg, Shon G. ;

Wang, Jianbin ;

Xia, Danny F. ;

Miller, Jeffrey C. ;

Urnov, Fyodor D. ;

Gregory, Philip D. ;

Holmes, Michael C. .

NATURE METHODS, 2011, 8 (01) :74-U108

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