A PDX/Organoid Biobank of Advanced Prostate Cancers Captures Genomic and Phenotypic Heterogeneity for Disease Modeling and Therapeutic Screening

被引：161

作者：

Beshiri, Michael L. ^{[1
]}

Tice, Caitlin M. ^{[1
]}

Tran, Crystal ^{[1
]}

Nguyen, Holly M. ^{[2
]}

Sowalsky, Adam G. ^{[1
]}

Agarwal, Supreet ^{[1
]}

Jansson, Keith H. ^{[1
]}

Yang, Qi ^{[1
]}

McGowen, Kerry M. ^{[1
]}

Yin, JuanJuan ^{[1
]}

Alilin, Aian Neil ^{[1
]}

Karzai, Fatima H. ^{[3
]}

Dahut, William L. ^{[3
]}

Corey, Eva ^{[2
]}

Kelly, Kathleen ^{[1
]}

机构：

[1] NCI, Lab Genitourinary Canc Pathogenesis, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[2] Univ Washington, Dept Urol, Seattle, WA 98195 USA

[3] NCI, Genitourinary Malignancies Branch, NIH, Bethesda, MD 20892 USA

来源：

CLINICAL CANCER RESEARCH | 2018年 / 24卷 / 17期

关键词：

ORGANOID CULTURES; KINASE INHIBITORS; TUMOR XENOGRAFTS; MOUSE MODELS; GSK3-BETA; EVOLUTION; CELLS; MAP; PHOSPHORYLATION; INACTIVATION;

D O I：

10.1158/1078-0432.CCR-18-0409

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: Prostate cancer translational research has been hampered by the lack of comprehensive and tractable models that represent the genomic landscape of clinical disease. Metastatic castrate-resistant prostate cancer (mCRPC) patient-derived xenografts (PDXs) recapitulate the genetic and phenotypic diversity of the disease. We sought to establish a representative, preclinical platform of PDX-derived organoids that is experimentally facile for high-throughput and mechanistic analysis. Experimental Design: Using 20 models from the LuCaP mCRPC PDX cohort, including adenocarcinoma and neuroendocrine lineages, we systematically tested >20 modifications to prostate organoid conditions. Organoids were evaluated for genomic and phenotypic stability and continued reliance on the AR signaling pathway. The utility of the platform as a genotype-dependent model of drug sensitivity was tested with olaparib and carboplatin. Results: All PDX models proliferated as organoids in culture. Greater than 50% could be continuously cultured long-tern in modified conditions; however, none of the PDXs could be established long-term as organoids under previously reported conditions. In addition, the modified conditions improved the establishment of patient biopsies over current methods. The genomic heterogeneity of the PDXs was conserved in organoids. lineage markers and transcriptomes were maintained between PDXs and organoids. Dependence on AR signaling was preserved in adenocarcinoma organoids, replicating a dominant characteristic of CRPC. Finally, we observed maximum cytotoxicity to the PARP inhibitor olaparib in BRCA2(-/-) organoids, similar to responses observed in patients. Conclusions: The LuCaP PDX/organoid models provide an expansive, genetically characterized platform to investigate the mechanisms of pathogenesis as well as therapeutic responses and their molecular correlates in mCRPC. (C) 2018 AACR.

引用

页码：4332 / 4345

页数：14

共 45 条

[1] The Molecular Taxonomy of Primary Prostate Cancer [J].

Abeshouse, Adam ;

Ahn, Jaeil ;

Akbani, Rehan ;

Ally, Adrian ;

Amin, Samirkumar ;

Andry, Christopher D. ;

Annala, Matti ;

Aprikian, Armen ;

Armenia, Joshua ;

Arora, Arshi ;

Auman, J. Todd ;

Balasundaram, Miruna ;

Balu, Saianand ;

Barbieri, Christopher E. ;

Bauer, Thomas ;

Benz, Christopher C. ;

Bergeron, Alain ;

Beroukhim, Rameen ;

Berrios, Mario ;

Bivol, Adrian ;

Bodenheimer, Tom ;

Boice, Lori ;

Bootwalla, Moiz S. ;

dos Reis, Rodolfo Borges ;

Boutros, Paul C. ;

Bowen, Jay ;

Bowlby, Reanne ;

Boyd, Jeffrey ;

Bradley, Robert K. ;

Breggia, Anne ;

Brimo, Fadi ;

Bristow, Christopher A. ;

Brooks, Denise ;

Broom, Bradley M. ;

Bryce, Alan H. ;

Bubley, Glenn ;

Burks, Eric ;

Butterfield, Yaron S. N. ;

Button, Michael ;

Canes, David ;

Carlotti, Carlos G. ;

Carlsen, Rebecca ;

Carmel, Michel ;

Carroll, Peter R. ;

Carter, Scott L. ;

Cartun, Richard ;

Carver, Brett S. ;

Chan, June M. ;

Chang, Matthew T. ;

Chen, Yu .

CELL, 2015, 163 (04) :1011-1025

[2] Examining the utility of patient-derived xenograft mouse models [J].

Aparicio, Samuel ;

Hidalgo, Manuel ;

Kung, Andrew L. .

NATURE REVIEWS CANCER, 2015, 15 (05) :311-316

[3] The selectivity of protein kinase inhibitors: a further update [J].

Bain, Jenny ;

Plater, Lorna ;

Elliott, Matt ;

Shpiro, Natalia ;

Hastie, C. James ;

Mclauchlan, Hilary ;

Klevernic, Iva ;

Arthur, J. Simon C. ;

Alessi, Dario R. ;

Cohen, Philip .

BIOCHEMICAL JOURNAL, 2007, 408 :297-315

[4] Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer [J].

Beltran, Himisha ;

Prandi, Davide ;

Mosquera, Juan Miguel ;

Benelli, Matteo ;

Puca, Loredana ;

Cyrta, Joanna ;

Marotz, Clarisse ;

Giannopoulou, Eugenia ;

Chakravarthi, Balabhadrapatruni V. S. K. ;

Varambally, Sooryanarayana ;

Tomlins, Scott A. ;

Nanus, David M. ;

Tagawa, Scott T. ;

Van Allen, Eliezer M. ;

Elemento, Olivier ;

Sboner, Andrea ;

Garraway, Levi A. ;

Rubin, Mark A. ;

Demichelis, Francesca .

NATURE MEDICINE, 2016, 22 (03) :298-305

[5] Patient-derived xenografts undergo mouse-specific tumor evolution [J].

Ben-David, Uri ;

Ha, Gavin ;

Tseng, Yuen-Yi ;

Greenwald, Noah F. ;

Oh, Coyin ;

Shih, Juliann ;

McFarland, James M. ;

Wong, Bang ;

Boehm, Jesse S. ;

Beroukhim, Rameen ;

Golub, Todd R. .

NATURE GENETICS, 2017, 49 (11) :1567-+

[6] p38 mitogen-activated protein kinase regulates canonical Wnt-β-catenin signaling by inactivation of GSK3β [J].

Bikkavilli, Rama Kamesh ;

Feigin, Michael E. ;

Malbon, Craig C. .

JOURNAL OF CELL SCIENCE, 2008, 121 (21) :3598-3607

[7] 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

[8] Spatial genomic heterogeneity within localized, multifocal prostate cancer [J].

Boutros, Paul C. ;

Fraser, Michael ;

Harding, Nicholas J. ;

de Borja, Richard ;

Trudel, Dominique ;

Lalonde, Emilie ;

Meng, Alice ;

Hennings-Yeomans, Pablo H. ;

McPherson, Andrew ;

Sabelnykova, Veronica Y. ;

Zia, Amin ;

Fox, Natalie S. ;

Livingstone, Julie ;

Shiah, Yu-Jia ;

Wang, Jianxin ;

Beck, Timothy A. ;

Have, Cherry L. ;

Chong, Taryne ;

Sam, Michelle ;

Johns, Jeremy ;

Timms, Lee ;

Buchner, Nicholas ;

Wong, Ada ;

Watson, John D. ;

Simmons, Trent T. ;

P'ng, Christine ;

Zafarana, Gaetano ;

Nguyen, Francis ;

Luo, Xuemei ;

Chu, Kenneth C. ;

Prokopec, Stephenie D. ;

Sykes, Jenna ;

Dal Pra, Alan ;

Berlin, Alejandro ;

Brown, Andrew ;

Chan-Seng-Yue, Michelle A. ;

Yousif, Fouad ;

Denroche, Robert E. ;

Chong, Lauren C. ;

Chen, Gregory M. ;

Jung, Esther ;

Fung, Clement ;

Starmans, Maud H. W. ;

Chen, Hanbo ;

Govind, Shaylan K. ;

Hawley, James ;

D'Costa, Alister ;

Pintilie, Melania ;

Waggott, Daryl ;

Hach, Faraz .

NATURE GENETICS, 2015, 47 (07) :736-+

[9] Human primary liver cancer-derived organoid cultures for disease modeling and drug screening [J].

Broutier, Laura ;

Mastrogiovanni, Gianmarco ;

Verstegen, Monique M. A. ;

Francies, Hayley E. ;

Gavarro, Lena Morrill ;

Bradshaw, Charles R. ;

Allen, George E. ;

Arnes-Benito, Robert ;

Sidorova, Olga ;

Gaspersz, Marcia P. ;

Georgakopoulos, Nikitas ;

Koo, Bon-Kyoung ;

Dietmann, Sabine ;

Davies, Susan E. ;

Praseedom, Raaj K. ;

Lieshout, Ruby ;

IJzermans, Jan N. M. ;

Wigmore, Stephen J. ;

Saeb-Parsy, Kourosh ;

Garnett, Mathew J. ;

van der Laan, Luc J. W. ;

Huch, Meritxell .

NATURE MEDICINE, 2017, 23 (12) :1424-+

[10] Organoid culture systems for prostate epithelial and cancer tissue [J].

Drost, Jarno ;

Karthaus, Wouter R. ;

Gao, Dong ;

Driehuis, Else ;

Sawyers, Charles L. ;

Chen, Yu ;

Clevers, Hans .

NATURE PROTOCOLS, 2016, 11 (02) :347-358

← 1 2 3 4 5 →