Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell– and patient-derived tumor organoids (original) (raw)

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Acknowledgements

We thank members of S.K.M.'s laboratory for helpful suggestions and discussions, D. Barsyte-Lovejoy for helping with epigenetic drug screening experiments and members of the PanCuRx team, including D. Hedley, for support and assistance. This work was supported by the Ontario Institute for Cancer Research (OICR) PanCuRx program; Canadian Cancer Society; Lee K Margaret Lau Chair for Breast Cancer Research and Campbell Family Institute for Breast cancer research to S.K.M. The Structural Genomics Consortium is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA) (ULTRA-DD grant 115766), Janssen, Merck and Co., Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation (FAPESP), Takeda, and the Wellcome Trust. This was also funded in part by the Ontario Ministry of Health and Long Term Care (OMOHLTC). The views expressed do not necessarily reflect those of the OMOHLTC.

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Author notes

1. Audrey Holtzinger and Ishaan Jagan: These authors contributed equally to this work.

Authors and Affiliations

1. Princess Margaret Cancer Center, University Health Network (UHN), University of Toronto, Toronto, Ontario, Canada
   Ling Huang, Audrey Holtzinger, Ishaan Jagan, Michael BeGora, Ines Lohse, Nicholas Ngai, Cristina Nostro, Lakshmi B Muthuswamy, Cheryl Arrowsmith, Michael Roehrl, Ming-Sound Tsao, Gordon Keller & Senthil K Muthuswamy
2. McEwen Center for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada
   Audrey Holtzinger, Cristina Nostro & Gordon Keller
3. Department of Physiology, Western University, London, Ontario, Canada
   Rennian Wang
4. Department of Pharmacology, Western University, London, Ontario, Canada
   Rennian Wang
5. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
   Howard C Crawford
6. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
   Howard C Crawford
7. Structural Genomics Consortium, Toronto, Ontario, Canada
   Cheryl Arrowsmith
8. Division of Anatomic Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada
   Steve E Kalloger & David F Schaeffer
9. Department of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada
   Steve E Kalloger, Daniel J Renouf & David F Schaeffer
10. Pancreas Centre British Columbia, Vancouver, British Columbia, Canada
    Steve E Kalloger, Daniel J Renouf & David F Schaeffer
11. Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
    Daniel J Renouf
12. Division of General Surgery, University of Toronto, Toronto, Ontario, Canada
    Ashton A Connor, Sean Cleary & Steven Gallinger
13. Department of Pathology, University Health Network, Toronto, Ontario, Canada
    Ming-Sound Tsao

Authors

1. Ling Huang
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2. Audrey Holtzinger
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3. Ishaan Jagan
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4. Michael BeGora
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5. Ines Lohse
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6. Nicholas Ngai
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7. Cristina Nostro
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8. Rennian Wang
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9. Lakshmi B Muthuswamy
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10. Howard C Crawford
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11. Cheryl Arrowsmith
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12. Steve E Kalloger
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13. Daniel J Renouf
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14. Ashton A Connor
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15. Sean Cleary
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16. David F Schaeffer
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17. Michael Roehrl
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18. Ming-Sound Tsao
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19. Steven Gallinger
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20. Gordon Keller
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21. Senthil K Muthuswamy
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Contributions

S.K.M. conceived and coordinated the project, designed experiments and co-wrote the manuscript with L.H. L.H. also designed, performed and/or coordinated all experiments. G.K. and A.H. contributed to pancreatic lineage–committed precursor generation. I.J. contributed tumor organoid live imaging and manuscript preparation. M.B. contributed to tumor organoid immunofluorescence microscopy. I.L. contributed to collection of patient-derived xenograft tumors. N.N. contributed to organoid size measurement. C.N. contributed to pancreatic lineage–committed precursor generation. R.W. contributed to human fetal pancreas studies. L.B.M. contributed to bioinformatics analysis for gene expressions. H.C.C. contributed to experimental design. C.A. contributed to epigenetic drug screening. S.E.K., D.J.R., A.A.C., S.C. and D.F.S. contributed to studies of P53 and SOX9 localization in patient samples. M.R. contributed to pathological analysis on patient tumor and tumor organoids, and studies of P53 and SOX9 localization in patient samples. M.-S.T. contributed to pathological analysis on patient tumor and tumor organoids, and studies of P53 and SOX9 localization in patient samples. S.G. contributed to obtaining patient resections for tumor organoid.

Corresponding author

Correspondence toSenthil K Muthuswamy.

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The authors declare no competing financial interests.

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Huang, L., Holtzinger, A., Jagan, I. et al. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell– and patient-derived tumor organoids.Nat Med 21, 1364–1371 (2015). https://doi.org/10.1038/nm.3973

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• Received: 25 June 2015
• Accepted: 12 September 2015
• Published: 26 October 2015
• Issue Date: November 2015
• DOI: https://doi.org/10.1038/nm.3973