Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer

被引：773

作者：

Tiriac, Herve ^{[1
]}

Belleau, Pascal ^{[1
]}

Engle, Dannielle D. ^{[1
]}

Plenker, Dennis ^{[1
]}

Deschenes, Astrid ^{[1
]}

Somerville, Tim D. D. ^{[1
]}

Froeling, Fieke E. M. ^{[1
]}

Burkhart, Richard A. ^{[2
]}

Denroche, Robert E. ^{[3
]}

Jang, Gun-Ho ^{[3
]}

Miyabayashi, Koji ^{[1
]}

Young, C. Megan ^{[1
,4
]}

Patel, Hardik ^{[1
]}

Ma, Michelle ^{[1
]}

LaComb, Joseph F. ^{[5
]}

Palmaira, Randze Lerie D. ^{[6
]}

Javed, Ammar A. ^{[2
]}

Huynh, Jasmine C. ^{[7
]}

Johnson, Molly ^{[8
]}

Arora, Kanika ^{[8
]}

Robine, Nicolas ^{[8
]}

Shah, Minita ^{[8
]}

Sanghvi, Rashesh ^{[8
]}

Goetz, Austin B. ^{[9
]}

Lowder, Cinthya Y. ^{[9
]}

Martello, Laura ^{[10
]}

Driehuis, Else ^{[11
,12
]}

LeComte, Nicolas ^{[6
]}

Askan, Gokce ^{[6
]}

Iacobuzio-Donahue, Christine A. ^{[6
]}

Clevers, Hans ^{[11
,12
,13
]}

Wood, Laura D. ^{[14
]}

Hruban, Ralph H. ^{[14
]}

Thompson, Elizabeth ^{[14
]}

Aguirre, Andrew J. ^{[15
]}

Wolpin, Brian M. ^{[15
]}

Sasson, Aaron ^{[16
]}

Kim, Joseph ^{[16
]}

Wu, Maoxin ^{[17
]}

Bucobo, Juan Carlos ^{[5
]}

Allen, Peter ^{[6
]}

Sejpal, Divyesh V. ^{[18
]}

Nealon, William ^{[19
]}

Sullivan, James D. ^{[19
]}

Winter, Jordan M. ^{[9
]}

Gimotty, Phyllis A. ^{[20
]}

Grem, Jean L. ^{[21
]}

DiMaio, Dominick J. ^{[22
]}

Buscaglia, Jonathan M. ^{[5
]}

Grandgenett, Paul M. ^{[23
]}

机构：

[1] Cold Spring Harbor Lab, 1 Bungtown Rd, Cold Spring Harbor, NY 11724 USA

[2] Johns Hopkins Univ, Div Hepatobiliary & Pancreat Surg, Baltimore, MD USA

[3] Ontario Inst Canc Res, PanCuRx Translat Res Initiat, Toronto, ON, Canada

[4] Swiss Inst Expt Canc Res ISREC, Sch Life Sci, Swiss Fed Inst Technol Lausanne EPFL, Lab Tumor Heterogene & Stemness Canc, Lausanne, Switzerland

[5] SUNY Stony Brook, Dept Med, Stony Brook, NY 11794 USA

[6] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA

[7] Univ Calif Davis, Ctr Comprehens Canc, Div Hematol & Oncol, Sacramento, CA 95817 USA

[8] New York Genome Ctr, New York, NY USA

[9] Thomas Jefferson Univ, Dept Surg, Philadelphia, PA 19107 USA

[10] Suny Downstate Med Ctr, Dept Med, New York, NY USA

[11] Royal Netherlands Acad Arts & Sci KNAW, Hubrecht Inst, Utrecht, Netherlands

[12] UMC, Utrecht, Netherlands

[13] PMC, Utrecht, Netherlands

[14] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA

[15] Broad Inst, Dana Farber Canc Inst, Boston, MA USA

[16] SUNY Stony Brook, Dept Surg, Stony Brook, NY 11794 USA

[17] SUNY Stony Brook, Dept Pathol, Stony Brook, NY 11794 USA

[18] Donald & Barbara Zucker Sch Med Hofstra Northwell, Div Gastroenterol, Hempstead, NY USA

[19] Donald & Barbara Zucker Sch Med Hofstra Northwell, Dept Surg, Hempstead, NY USA

[20] Univ Penn, Dept Biostat Epidemiol & Informat, Philadelphia, PA 19104 USA

[21] Univ Nebraska Med Ctr, Dept Med, Omaha, NE USA

[22] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA

[23] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Fred & Pamela Buffet Canc Ctr, Omaha, NE USA

[24] Univ Toronto, Univ Hlth Network, Wallace McCain Ctr Pancreat Canc, Dept Med Oncol,Princess Margaret Canc Ctr, Toronto, ON, Canada

[25] Donald & Barbara Zucker Sch Med Hofstra Northwell, Dept Pathol & Lab Med, Hempstead, NY USA

[26] Donald & Barbara Zucker Sch Med Hofstra Northwell, Div Med Oncol, Hempstead, NY USA

[27] Weill Cornell Med Coll, New York, NY USA

[28] Univ Toronto, Univ Hlth Network, Dept Pathol, Toronto, ON, Canada

[29] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada

[30] SUNY Stony Brook, Dept Biomed Informat, Stony Brook, NY 11794 USA

[31] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada

[32] Univ Hlth Network, Hepatobiliary Pancreat Surg Oncol Program, Toronto, ON, Canada

来源：

CANCER DISCOVERY | 2018年 / 8卷 / 09期

关键词：

PAIRED-END; TUMOR; GEMCITABINE; SUBTYPES; MULTICENTER; INHIBITION; MUTATIONS; GENOMES;

D O I：

10.1158/2159-8290.CD-18-0349

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver onco-genes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection. SIGNIFICANCE: New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer. (C) 2018 AACR.

引用

页码：1112 / 1129

页数：18

共 63 条

[31] Potentially Curable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline [J].

Khorana, Alok A. ;

Mangu, Pamela B. ;

Berlin, Jordan ;

Engebretson, Anitra ;

Hong, Theodore S. ;

Maitra, Anirban ;

Mohile, Supriya G. ;

Mumber, Matthew ;

Schulick, Richard ;

Shapiro, Marc ;

Urba, Susan ;

Zeh, Herbert J. ;

Katz, Matthew H. G. .

JOURNAL OF CLINICAL ONCOLOGY, 2016, 34 (21) :2541-+

[32] Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade [J].

Le, Dung T. ;

Durham, Jennifer N. ;

Smith, Kellie N. ;

Wang, Hao ;

Bartlett, Bjarne R. ;

Aulakh, Laveet K. ;

Lu, Steve ;

Kemberling, Holly ;

Wilt, Cara ;

Luber, Brandon S. ;

Wong, Fay ;

Azad, Nilofer S. ;

Rucki, Agnieszka A. ;

Laheru, Dan ;

Donehower, Ross ;

Zaheer, Atif ;

Fisher, George A. ;

Crocenzi, Todd S. ;

Lee, James J. ;

Greten, Tim F. ;

Duffy, Austin G. ;

Ciombor, Kristen K. ;

Eyring, Aleksandra D. ;

Lam, Bao H. ;

Joe, Andrew ;

Kang, S. Peter ;

Holdhoff, Matthias ;

Danilova, Ludmila ;

Cope, Leslie ;

Meyer, Christian ;

Zhou, Shibin ;

Goldberg, Richard M. ;

Armstrong, Deborah K. ;

Bever, Katherine M. ;

Fader, Amanda N. ;

Taube, Janis ;

Housseau, Franck ;

Spetzler, David ;

Xiao, Nianqing ;

Pardoll, Drew M. ;

Papadopoulos, Nickolas ;

Kinzler, Kenneth W. ;

Eshleman, James R. ;

Vogelstein, Bert ;

Anders, Robert A. ;

Diaz, Luis A., Jr. .

SCIENCE, 2017, 357 (6349) :409-413

[33] RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome [J].

Li, Bo ;

Dewey, Colin N. .

BMC BIOINFORMATICS, 2011, 12

[34] Fast and accurate short read alignment with Burrows-Wheeler transform [J].

Li, Heng ;

Durbin, Richard .

BIOINFORMATICS, 2009, 25 (14) :1754-1760

[35] Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 [J].

Love, Michael I. ;

Huber, Wolfgang ;

Anders, Simon .

GENOME BIOLOGY, 2014, 15 (12)

[36] The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data [J].

McKenna, Aaron ;

Hanna, Matthew ;

Banks, Eric ;

Sivachenko, Andrey ;

Cibulskis, Kristian ;

Kernytsky, Andrew ;

Garimella, Kiran ;

Altshuler, David ;

Gabriel, Stacey ;

Daly, Mark ;

DePristo, Mark A. .

GENOME RESEARCH, 2010, 20 (09) :1297-1303

[37] Active and water-soluble form of lipidated Wnt protein is maintained by a serum glycoprotein afamin/α-albumin [J].

Mihara, Emiko ;

Hirai, Hidenori ;

Yamamoto, Hideki ;

Tamura-Kawakami, Keiko ;

Matano, Mami ;

Kikuchi, Akira ;

Sato, Toshiro ;

Takagi, Junichi .

ELIFE, 2016, 5

[38] Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma [J].

Moffitt, Richard A. ;

Marayati, Raoud ;

Flate, Elizabeth L. ;

Volmar, Keith E. ;

Loeza, S. Gabriela Herrera ;

Hoadley, Katherine A. ;

Rashid, Naim U. ;

Williams, Lindsay A. ;

Eaton, Samuel C. ;

Chung, Alexander H. ;

Smyla, Jadwiga K. ;

Anderson, Judy M. ;

Kim, Hong Jin ;

Bentrem, David J. ;

Talamonti, Mark S. ;

Iacobuzio-Donahue, Christine A. ;

Hollingsworth, Michael A. ;

Yeh, Jen Jen .

NATURE GENETICS, 2015, 47 (10) :1168-+

[39]

Narzisi G, 2014, NAT METHODS, V11, P1033, DOI [10.1038/NMETH.3069, 10.1038/nmeth.3069]

[40] Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial [J].

Neoptolemos, John P. ;

Palmer, Daniel H. ;

Ghaneh, Paula ;

Psarelli, Eftychia E. ;

Valle, Juan W. ;

Halloran, Christopher M. ;

Faluyi, Olusola ;

O'Reilly, Derek A. ;

Cunningham, David ;

Wadsley, Jonathan ;

Darby, Suzanne ;

Meyer, Tim ;

Gillmore, Roopinder ;

Anthoney, Alan ;

Lind, Pehr ;

Glimelius, Bengt ;

Falk, Stephen ;

Izbicki, Jakob R. ;

Middleton, Gary William ;

Cummins, Sebastian ;

Ross, Paul J. ;

Wasan, Harpreet ;

McDonald, Alec ;

Crosby, Tom ;

Ma, Yuk Ting ;

Patel, Kinnari ;

Sherriff, David ;

Soomal, Rubin ;

Borg, David ;

Sothi, Sharmila ;

Hammel, Pascal ;

Hackert, Thilo ;

Jackson, Richard ;

Buechler, Markus W. .

LANCET, 2017, 389 (10073) :1011-1024

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