Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer
Open accessPublished version of a preprint
Abstract
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 oncogenes 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. Cancer Discov; 8(9); 1112–29. ©2018 AACR. See related commentary by Collisson, p. 1062. This article is highlighted in the In This Issue feature, p. 1047
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For pancreatic ductal adenocarcinoma, 114 PDO cultures from 101 patients underwent transcriptomic and drug-response profiling.
“114 PDO cultures from 101 patients were generated127 and subjected to transcriptomic profiling, followed by therapeutic profiling”
From Human disease models in drug development (2023) · cites this paper as [127]
The Results section, “Assembling a pancreatic cancer patient-derived organoid library” (page unavailable), reports 114 PDO cultures generated from 101 patients. But “Transcriptomic profiling and subtyping” reports RNA sequencing of 44 PDAC-confirmed PDOs, and “PDO pharmacotyping corresponds with individual patient treatment responses” reports therapeutic profiling of 66. The source does not support the implication that all 114 underwent both types of profiling. (LLM, conf=0.92)
Experimental — accuracy not yet measuredPancreatic ductal adenocarcinoma PDO treatment outcomes correlated positively with individual patient responses.
“The treatment outcome of the PDOs positively correlated with individual patient responses”
From Human disease models in drug development (2023) · cites this paper as [127]
Patient-derived tumoroid models show promise in testing drug efficacy and potentially determining a personalized treatment for the patient.
“patient-derived tumoroid models also show promise in testing drug efficacy and potentially determining a personalized treatment for the patient7–12.”
From One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids (2023) · cites this paper as [10]
Heterogeneity in treatment responses is being exploited for the treatment of cystic fibrosis patients, with a large ongoing European multicentre clinical trial led by the HIT-Cystic Fibrosis consortium to identify potential responders.
“This heterogeneity in treatment responses is now being exploited for the treatment of cystic fibrosis patients191, with a large ongoing European multicentre clinical trial study, led by the HIT-Cystic Fibrosis consortium, to identify potential responders214.”
From Organoids (2022) · cites this paper as [214]
Citation 214 is attached to the claim about a European multicentre cystic fibrosis trial led by the HIT-Cystic Fibrosis consortium. The Discussion describes identifying chemotherapy responders among pancreatic cancer patients, but searches for the consortium, cystic fibrosis, and the European trial found no passage addressing that trial. (LLM, conf=0.76)
Experimental — accuracy not yet measuredNormal and tumor organoid models have been developed from human and mouse pancreas.
“Recently, normal and tumor organoid models have been developed from both human and mouse pancreas (82, 83).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [83]
Recent technological advancements (e.g. organoid models and conditionally reprogrammed cell lines) have led to a new generation of cancer cell models being derived to allow full representation of the histopathological and molecular diversity of tumours.
“Furthermore, with recent technological advancements (e.g. organoid models and conditionally reprogrammed cell lines), a new generation of cancer cell models is being derived to allow full representation of the histopathological and molecular diversity of tumours (37–42).”
From Cell Model Passports-a hub for clinical, genetic and functional datasets of preclinical cancer models (2019) · cites this paper as [40]
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Tang, M., Tiwari, S. K., Agrawal, K., Tan, M. L., Dang, J. W., Tam, T., Tian, J., Wan, X., Schimelman, J. B., You, S., et al. (2021) · Small · doi:10.1002/smll.202006050 · Cited by 126 · see citing works
SOAT1 promotes mevalonate pathway dependency in pancreatic cancer
Oni, T. E., Biffi, G., Baker, L. A., Yuan, H., Tonelli, C., Somerville, T. D. D., Deschênes, A., Belleau, P., Hwang, C., Rivera, F. J. S., et al. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20192389 · Cited by 124 · see citing works
Self-citationCancer research using organoid technology
Kretzschmar, K. (2021) · Journal of Molecular Medicine · doi:10.1007/s00109-020-01990-z · Cited by 120 · see citing works
Farin, H. F., Mosa, M. H., Ndreshkjana, B., Grebbin, B. M., Ritter, B., Menche, C., Kennel, K. B., Ziegler, P. K., Szabó, L., Bollrath, J., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0050 · Cited by 120 · see citing works
Millen, R., de Kort, W. W. B., Koomen, M., van Son, G. J. F., Gobits, R., de Vries, B. B. L. P., Begthel, H., Zandvliet, M. M. J. M., Doornaert, P., Raaijmakers, C. P. J., et al. (2023) · Med · doi:10.1016/j.medj.2023.04.003 · Cited by 118 · see citing works
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- Authors
- Tiriac, H., Belleau, P., Engle, D. D., Plenker, D., Deschênes, A., Somerville, T. D. D., Froeling, F. E. M., Burkhart, R. A., Denroche, R. E., Jang, G.-H., Miyabayashi, K., Young, C. M., Patel, H., Ma, M., LaComb, J. F., Palmaira, R. L. D., Javed, A. A., Huynh, J. C., Johnson, M., Arora, K., Robine, N., Shah, M., Sanghvi, R., Goetz, A. B., Lowder, C. Y., Martello, L., Driehuis, E., LeComte, N., Askan, G., Iacobuzio-Donahue, C. A., Clevers, H., Wood, L. D., Hruban, R. H., Thompson, E., Aguirre, A. J., Wolpin, B. M., Sasson, A., Kim, J., Wu, M., Bucobo, J. C., Allen, P., Sejpal, D. V., Nealon, W., Sullivan, J. D., Winter, J. M., Gimotty, P. A., Grem, J. L., DiMaio, D. J., Buscaglia, J. M., Grandgenett, P. M., Brody, J. R., Hollingsworth, M. A., O'Kane, G. M., Notta, F., Kim, E., Crawford, J. M., Devoe, C., Ocean, A., Wolfgang, C. L., Yu, K. H., Li, E., Vakoc, C. R., Hubert, B., Fischer, S. E., Wilson, J. M., Moffitt, R., Knox, J., Krasnitz, A., Gallinger, S., & Tuveson, D. A.
- Affiliations
- Cold Spring Harbor Laboratory (US)
- Johns Hopkins University (US)
- Ontario Institute for Cancer Research (CA)
- Stony Brook University (US)
- Memorial Sloan Kettering Cancer Center (US)
- UC Davis Comprehensive Cancer Center (US)
- New York Genome Center (US)
- Thomas Jefferson University (US)
- SUNY Downstate Health Sciences University (US)
- Royal Netherlands Academy of Arts and Sciences (NL)
- 6Memorial Sloan Kettering Cancer Center, New York, New York.
- Broad Institute (US)
- Hofstra University (US)
- Donald & Barbara Zucker School of Medicine at Hofstra/Northwell (US)
- University of Pennsylvania (US)
- University of Nebraska Medical Center (US)
- Nebraska Medical Center (US)
- University Health Network (CA)
- Weill Cornell Medicine (US)
- 3PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
- Corresponding author
- Tuveson, David A.
- ORCID
- Tiriac, Hervé
- Engle, Dannielle D.
- Plenker, Dennis
- Deschênes, Astrid
- Somerville, Tim D. D.
- Froeling, Fieke E. M.
- Burkhart, Richard A.
- Denroche, Robert E.
- Jang, Gun-Ho
- Miyabayashi, Koji
- Young, C. Megan
- LaComb, Joseph F.
- Javed, Ammar A.
- Huynh, Jasmine C.
- Johnson, Molly
- Arora, Kanika
- Robine, Nicolas
- Sanghvi, Rashesh
- Lowder, Cinthya Y.
- Martello, Laura
- Driehuis, Else
- LeComte, Nicolas
- Clevers, Hans
- Wood, Laura D.
- Hruban, Ralph H.
- Aguirre, Andrew J.
- Wolpin, Brian M.
- Kim, Joseph
- Wu, Maoxin
- Bucobo, Juan Carlos
- Nealon, William
- Winter, Jordan M.
- Gimotty, Phyllis A.
- Grem, Jean L.
- DiMaio, Dominick J.
- Buscaglia, Jonathan M.
- Grandgenett, Paul M.
- Brody, Jonathan R.
- Hollingsworth, Michael A.
- O'Kane, Grainne M.
- Notta, Faiyaz
- Kim, Edward
- Crawford, James M.
- Devoe, Craig
- Ocean, Allyson
- Wolfgang, Christopher L.
- Yu, Kenneth H.
- Li, Ellen
- Vakoc, Christopher R.
- Fischer, Sandra E.
- Wilson, Julie M.
- Moffitt, Richard
- Knox, Jennifer
- Krasnitz, Alexander
- Tuveson, David A.
- Venue
- Cancer Discovery
- Published
- 2018-09-01
- Volume
- 8
- Issue
- 9
- Pages
- 1112-1129
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC6125219
- OpenAlex
- W2807088563
- Cited by
- 1,092
- References
- 62
- Citations by year
- 2026: 132 · 2025: 135 · 2024: 147 · 2023: 130 · 2022: 150 · 2021: 168 · 2020: 128 · 2019: 83 · 2018: 16
- FWCI
- 36.76
- Type
- journal article
- Language
- en
- Open access
- green
- pure.knaw.nl
- Licence
- other-oa
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- HHS | National Institutes of Health (NIH) (5P30CA45508-29, 5P50CA101955-07, P20CA192996-03, 1U10CA180944-04, 5U01CA168409-5, 1R01CA188134-01, 1R01CA190092-04, HHSN26100008)
- Lustgarten Foundation
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- pancreatic cancer, patient-derived organoids, chemotherapy response, chemotherapy response prediction, predictive biomarkers, transcriptomic subtypes, cancer driver genes, gene expression signatures, synchronous metastases, chemotherapy-refractory disease, targeted therapy, precision medicine, adjuvant chemotherapy
- MeSH terms
- Antineoplastic Agents, Drug Screening Assays, Antitumor, Humans, Organoids, Pancreatic Neoplasms, Prospective Studies, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Sequence Analysis, RNA, Drug Resistance, Neoplasm, Gene Expression Profiling, Gene Regulatory Networks, Precision Medicine, Molecular Targeted Therapy, Standard of Care
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