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Human primary liver cancer organoids reveal intratumor and interpatient drug response heterogeneity
Ling Li, … , Joel S. Bader, Florin M. Selaru
Ling Li, … , Joel S. Bader, Florin M. Selaru
Published January 24, 2019
Citation Information: JCI Insight. 2019;4(2):e121490. https://doi.org/10.1172/jci.insight.121490.
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Categories: Research Article Hepatology Oncology

Human primary liver cancer organoids reveal intratumor and interpatient drug response heterogeneity

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Abstract

Liver cancer is the fourth leading cause of cancer-related mortality and is distinguished by a relative paucity of chemotherapy options. It has been hypothesized that intratumor genetic heterogeneity may contribute to the high failure rate of chemotherapy. Here, we evaluated functional heterogeneity in a cohort of primary human liver cancer organoid lines. Each primary human liver cancer surgical specimen was used to generate multiple cancer organoid lines, obtained from distinct regions of the tumor. A total of 27 liver cancer lines were established and tested with 129 cancer drugs, generating 3,483 cell survival data points. We found a rich intratumor, functional (drug response) heterogeneity in our liver cancer patients. Furthermore, we established that the majority of drugs were either ineffective, or effective only in select organoid lines. In contrast, we found that a subset of drugs appeared pan-effective, displaying at least moderate activity in the majority of these cancer organoid lines. These drugs, which are FDA approved for indications other than liver cancers, deserve further consideration as either systemic or local therapeutics. Of note, molecular profiles, obtained for a reduced sample set, did not correlate with the drug response heterogeneity of liver cancer organoid lines. Taken together, these findings lay the foundation for in-depth studies of pan-effective drugs, as well as for functional personalized oncology approaches. Lastly, these functional studies demonstrate the utility of cancer organoid drug testing as part of a drug discovery pipeline.

Authors

Ling Li, Hildur Knutsdottir, Ken Hui, Matthew J. Weiss, Jin He, Benjamin Philosophe, Andrew M. Cameron, Christopher L. Wolfgang, Timothy M. Pawlik, Gabriel Ghiaur, Andrew J. Ewald, Esteban Mezey, Joel S. Bader, Florin M. Selaru

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Figure 1

Establishment of multiregion organoid lines from a primary human liver cancer.

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Establishment of multiregion organoid lines from a primary human liver c...
(A) A cancer resection piece was cut into 20 tissue slices. The white-yellow appearance of the tissue in most of the slices was found to be fibrotic, intrahepatic cholangiocarcinoma. These tissue slices were utilized for histological, tissue banking, organoid establishment, and other analyses. (B) Bright-light images of PDOs established from CCA8. Cystic patient–derived organoid (PDO) structures were recognized starting on day 2 (D, day; P, passage). A representative cystic PDO was photographed from D1 to D10, at which point the culture was split. Representative images for this PDO culture are shown at P3 as well as P6. (C and D) Immunofluorescence staining of primary human cancer tissue and a matched PDO established from the same tissue slice for EPCAM (epithelial marker), CK19 (bile duct marker), and LGR5 and SOX9 (stem cell markers). DAPI was used to stain nuclei. (E and F) Primary human cancer tissue and a matched PDO established from the same tissue slice was used for hematoxylin and eosin staining as well as for immunohistochemistry (CK7 is a bile duct marker, and mucicarmine is a mucin marker). Scale bars: 200 μm (B) and 100 μm (C–F).
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Copyright © 2019 American Society for Clinical Investigation
ISSN 2379-3708

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