Organoid models of human and mouse ductal pancreatic cancer

Sylvia F. Boj; Chang Il Hwang; Lindsey A. Baker; Iok In Christine Chio; Dannielle D. Engle; Vincenzo Corbo; Myrthe Jager; Mariano Ponz-Sarvise; Hervé Tiriac; Mona S. Spector; Ana Gracanin; Tobiloba Oni; Kenneth H. Yu; Ruben Van Boxtel; Meritxell Huch; Keith D. Rivera; John P. Wilson; Michael E. Feigin; Daniel Öhlund; Abram Handly-Santana; Christine M. Ardito-Abraham; Michael Ludwig; Ela Elyada; Brinda Alagesan; Giulia Biffi; Georgi N. Yordanov; Bethany Delcuze; Brianna Creighton; Kevin Wright; Youngkyu Park; Folkert H.M. Morsink; I. Quintus Molenaar; Inne H. Borel Rinkes; Edwin Cuppen; Yuan Hao; Ying Jin; Isaac J. Nijman; Christine Iacobuzio-Donahue; Steven D. Leach; Darryl J. Pappin; Molly Hammell; David S. Klimstra; Olca Basturk; Ralph H. Hruban; George Johan Offerhaus; Robert G.J. Vries; Hans Clevers; David A. Tuveson

doi:10.1016/j.cell.2014.12.021

Organoid models of human and mouse ductal pancreatic cancer

Sylvia F. Boj, Chang Il Hwang, Lindsey A. Baker, Iok In Christine Chio, Dannielle D. Engle, Vincenzo Corbo, Myrthe Jager, Mariano Ponz-Sarvise, Hervé Tiriac, Mona S. Spector, Ana Gracanin, Tobiloba Oni, Kenneth H. Yu, Ruben Van Boxtel, Meritxell Huch, Keith D. Rivera, John P. Wilson, Michael E. Feigin, Daniel Öhlund, Abram Handly-SantanaChristine M. Ardito-Abraham, Michael Ludwig, Ela Elyada, Brinda Alagesan, Giulia Biffi, Georgi N. Yordanov, Bethany Delcuze, Brianna Creighton, Kevin Wright, Youngkyu Park, Folkert H.M. Morsink, I. Quintus Molenaar, Inne H. Borel Rinkes, Edwin Cuppen, Yuan Hao, Ying Jin, Isaac J. Nijman, Christine Iacobuzio-Donahue, Steven D. Leach, Darryl J. Pappin, Molly Hammell, David S. Klimstra, Olca Basturk, Ralph H. Hruban, George Johan Offerhaus, Robert G.J. Vries, Hans Clevers, David A. Tuveson

School of Medicine

Research output: Contribution to journal › Article › peer-review

825 Scopus citations

Abstract

Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy.

Original language	English (US)
Pages (from-to)	324-338
Number of pages	15
Journal	Cell
Volume	160
Issue number	1-2
DOIs	https://doi.org/10.1016/j.cell.2014.12.021
State	Published - Jan 15 2015

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.cell.2014.12.021

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Boj, S. F., Hwang, C. I., Baker, L. A., Chio, I. I. C., Engle, D. D., Corbo, V., Jager, M., Ponz-Sarvise, M., Tiriac, H., Spector, M. S., Gracanin, A., Oni, T., Yu, K. H., Van Boxtel, R., Huch, M., Rivera, K. D., Wilson, J. P., Feigin, M. E., Öhlund, D., ... Tuveson, D. A. (2015). Organoid models of human and mouse ductal pancreatic cancer. Cell, 160(1-2), 324-338. https://doi.org/10.1016/j.cell.2014.12.021

Boj, SF, Hwang, CI, Baker, LA, Chio, IIC, Engle, DD, Corbo, V, Jager, M, Ponz-Sarvise, M, Tiriac, H, Spector, MS, Gracanin, A, Oni, T, Yu, KH, Van Boxtel, R, Huch, M, Rivera, KD, Wilson, JP, Feigin, ME, Öhlund, D, Handly-Santana, A, Ardito-Abraham, CM, Ludwig, M, Elyada, E, Alagesan, B, Biffi, G, Yordanov, GN, Delcuze, B, Creighton, B, Wright, K, Park, Y, Morsink, FHM, Molenaar, IQ, Borel Rinkes, IH, Cuppen, E, Hao, Y, Jin, Y, Nijman, IJ, Iacobuzio-Donahue, C, Leach, SD, Pappin, DJ, Hammell, M, Klimstra, DS, Basturk, O, Hruban, RH, Offerhaus, GJ, Vries, RGJ, Clevers, H & Tuveson, DA 2015, 'Organoid models of human and mouse ductal pancreatic cancer', Cell, vol. 160, no. 1-2, pp. 324-338. https://doi.org/10.1016/j.cell.2014.12.021

@article{1c3b9e019ea341788a7dda2f82c2d0b0,

title = "Organoid models of human and mouse ductal pancreatic cancer",

abstract = "Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy.",

author = "Boj, {Sylvia F.} and Hwang, {Chang Il} and Baker, {Lindsey A.} and Chio, {Iok In Christine} and Engle, {Dannielle D.} and Vincenzo Corbo and Myrthe Jager and Mariano Ponz-Sarvise and Herv{\'e} Tiriac and Spector, {Mona S.} and Ana Gracanin and Tobiloba Oni and Yu, {Kenneth H.} and {Van Boxtel}, Ruben and Meritxell Huch and Rivera, {Keith D.} and Wilson, {John P.} and Feigin, {Michael E.} and Daniel {\"O}hlund and Abram Handly-Santana and Ardito-Abraham, {Christine M.} and Michael Ludwig and Ela Elyada and Brinda Alagesan and Giulia Biffi and Yordanov, {Georgi N.} and Bethany Delcuze and Brianna Creighton and Kevin Wright and Youngkyu Park and Morsink, {Folkert H.M.} and Molenaar, {I. Quintus} and {Borel Rinkes}, {Inne H.} and Edwin Cuppen and Yuan Hao and Ying Jin and Nijman, {Isaac J.} and Christine Iacobuzio-Donahue and Leach, {Steven D.} and Pappin, {Darryl J.} and Molly Hammell and Klimstra, {David S.} and Olca Basturk and Hruban, {Ralph H.} and Offerhaus, {George Johan} and Vries, {Robert G.J.} and Hans Clevers and Tuveson, {David A.}",

note = "Funding Information: We thank Peter Kapitein and Jan Schuurman from Inspire 2 Live for helping to establish the collaboration between D.A.T. and H.C. We also thank H. Begthel and J. Korving for technical assistance. This work was performed with assistance from the CSHL Proteomic, Histology, DNA Sequencing, Antibody, and Bioinformatics Shared Resources, which are supported by the Cancer Center Support Grant 5P30CA045508. D.A.T. is a distinguished scholar of the Lustgarten Foundation and Director of the Lustgarten Foundation-designated Laboratory of Pancreatic Cancer Research. D.A.T. is also supported by the Cold Spring Harbor Laboratory Association, the Carcinoid Foundation, PCUK, and the David Rubinstein Center for Pancreatic Cancer Research at MSKCC. In addition, we are grateful for support from the following: Stand Up to Cancer/KWF (H.C.), the STARR foundation (I7-A718 for D.A.T.), DOD (W81XWH-13-PRCRP-IA for D.A.T.), the Sol Goldman Pancreatic Cancer Research Center (R.H.H.), the Italian Ministry of Health (FIRB - RBAP10AHJ for V.C.), Sociedad Espa{\~n}ola de Oncolog{\'i}a M{\'e}dica (SEOM for M.P.S.), Louis Morin Charitable Trust (M.E.F.), the Swedish Research Council (537-2013-7277 for D.{\"O}.), The Kempe Foundations (JCK-1301 for D.{\"O}.) and the Swedish Society of Medicine (SLS-326921, SLS-250831 for D.{\"O}.), the Damon Runyon Cancer Research Foundation (DRG-2165-13 for I.I.C.C.), the Human Frontiers Science Program (LT000403/2014 for E.E.), the Weizmann Institute of Science Women in Science Award (E.E.), the American Cancer Society (PF-13-317-01-CSM for C.M.A.A.), the Hearst Foundation (A.H.S.), and the NIH (5P30CA45508-26, 5P50CA101955-07, 1U10CA180944-01, 5U01CA168409-3, and 1R01CA190092-01 for D.A.T.; CA62924 for R.H.H.; CA134292 for S.D.L.; 5T32CA148056 for L.A.B. and D.D.E.; and CA101955 UAB/UMN SPORE for L.A.B.). In addition, S.F.B. and M.H. are supported by KWF/PF-HUBR 2007-3956, A.G is supported by EU/232814-StemCellMark, and R.G.J.V. is supported by GenomiCs.nl (CGC). M.J., R.B., and E.C. are supported by the CancerGenomics.nl (NWO Gravitation) program. Ralph Hruban receives royalty payments from Myriad Genetics for the PalB2 inventions. Hans Clevers and Meritxell Huch have patents pending and granted on the organoid technology. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc. All rights reserved.",

year = "2015",

month = jan,

day = "15",

doi = "10.1016/j.cell.2014.12.021",

language = "English (US)",

volume = "160",

pages = "324--338",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "1-2",

}

TY - JOUR

T1 - Organoid models of human and mouse ductal pancreatic cancer

AU - Boj, Sylvia F.

AU - Hwang, Chang Il

AU - Baker, Lindsey A.

AU - Chio, Iok In Christine

AU - Engle, Dannielle D.

AU - Corbo, Vincenzo

AU - Jager, Myrthe

AU - Ponz-Sarvise, Mariano

AU - Tiriac, Hervé

AU - Spector, Mona S.

AU - Gracanin, Ana

AU - Oni, Tobiloba

AU - Yu, Kenneth H.

AU - Van Boxtel, Ruben

AU - Huch, Meritxell

AU - Rivera, Keith D.

AU - Wilson, John P.

AU - Feigin, Michael E.

AU - Öhlund, Daniel

AU - Handly-Santana, Abram

AU - Ardito-Abraham, Christine M.

AU - Ludwig, Michael

AU - Elyada, Ela

AU - Alagesan, Brinda

AU - Biffi, Giulia

AU - Yordanov, Georgi N.

AU - Delcuze, Bethany

AU - Creighton, Brianna

AU - Wright, Kevin

AU - Park, Youngkyu

AU - Morsink, Folkert H.M.

AU - Molenaar, I. Quintus

AU - Borel Rinkes, Inne H.

AU - Cuppen, Edwin

AU - Hao, Yuan

AU - Jin, Ying

AU - Nijman, Isaac J.

AU - Iacobuzio-Donahue, Christine

AU - Leach, Steven D.

AU - Pappin, Darryl J.

AU - Hammell, Molly

AU - Klimstra, David S.

AU - Basturk, Olca

AU - Hruban, Ralph H.

AU - Offerhaus, George Johan

AU - Vries, Robert G.J.

AU - Clevers, Hans

AU - Tuveson, David A.

N1 - Funding Information: We thank Peter Kapitein and Jan Schuurman from Inspire 2 Live for helping to establish the collaboration between D.A.T. and H.C. We also thank H. Begthel and J. Korving for technical assistance. This work was performed with assistance from the CSHL Proteomic, Histology, DNA Sequencing, Antibody, and Bioinformatics Shared Resources, which are supported by the Cancer Center Support Grant 5P30CA045508. D.A.T. is a distinguished scholar of the Lustgarten Foundation and Director of the Lustgarten Foundation-designated Laboratory of Pancreatic Cancer Research. D.A.T. is also supported by the Cold Spring Harbor Laboratory Association, the Carcinoid Foundation, PCUK, and the David Rubinstein Center for Pancreatic Cancer Research at MSKCC. In addition, we are grateful for support from the following: Stand Up to Cancer/KWF (H.C.), the STARR foundation (I7-A718 for D.A.T.), DOD (W81XWH-13-PRCRP-IA for D.A.T.), the Sol Goldman Pancreatic Cancer Research Center (R.H.H.), the Italian Ministry of Health (FIRB - RBAP10AHJ for V.C.), Sociedad Española de Oncología Médica (SEOM for M.P.S.), Louis Morin Charitable Trust (M.E.F.), the Swedish Research Council (537-2013-7277 for D.Ö.), The Kempe Foundations (JCK-1301 for D.Ö.) and the Swedish Society of Medicine (SLS-326921, SLS-250831 for D.Ö.), the Damon Runyon Cancer Research Foundation (DRG-2165-13 for I.I.C.C.), the Human Frontiers Science Program (LT000403/2014 for E.E.), the Weizmann Institute of Science Women in Science Award (E.E.), the American Cancer Society (PF-13-317-01-CSM for C.M.A.A.), the Hearst Foundation (A.H.S.), and the NIH (5P30CA45508-26, 5P50CA101955-07, 1U10CA180944-01, 5U01CA168409-3, and 1R01CA190092-01 for D.A.T.; CA62924 for R.H.H.; CA134292 for S.D.L.; 5T32CA148056 for L.A.B. and D.D.E.; and CA101955 UAB/UMN SPORE for L.A.B.). In addition, S.F.B. and M.H. are supported by KWF/PF-HUBR 2007-3956, A.G is supported by EU/232814-StemCellMark, and R.G.J.V. is supported by GenomiCs.nl (CGC). M.J., R.B., and E.C. are supported by the CancerGenomics.nl (NWO Gravitation) program. Ralph Hruban receives royalty payments from Myriad Genetics for the PalB2 inventions. Hans Clevers and Meritxell Huch have patents pending and granted on the organoid technology. Publisher Copyright: © 2015 Elsevier Inc. All rights reserved.

PY - 2015/1/15

Y1 - 2015/1/15

N2 - Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy.

AB - Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy.

UR - http://www.scopus.com/inward/record.url?scp=84920983131&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84920983131&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2014.12.021

DO - 10.1016/j.cell.2014.12.021

M3 - Article

C2 - 25557080

AN - SCOPUS:84920983131

SN - 0092-8674

VL - 160

SP - 324

EP - 338

JO - Cell

JF - Cell

IS - 1-2

ER -

Organoid models of human and mouse ductal pancreatic cancer

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