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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Research Article Hepatology Oncology

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

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 2

Low-throughput and high-throughput drug testing in cancer organoid lines and treatment efficacy determination, and summary of human primary liver cancer specimens, demographics, and laboratory derivation of sister PDO lines.

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Low-throughput and high-throughput drug testing in cancer organoid lines...
(A) A panel of 7 cancer drugs at a concentration of 10 μM, along with negative control (0.1% DMSO) and a positive control (10% Triton X-100), were used on a PDO line. The PDO treated with cisplatin appeared identical to the negative control, consistent with no drug efficacy. Gemcitabine stalls PDO growth, but does not kill cells. We verified that gemcitabine does not induce cell death through additional studies, as described in Supplemental Figure 2. (B) Cisplatin allows unrestricted growth of cancer PDOs — as demonstrated by continuously expanding cystic PDO structures — while gemcitabine had a cytostatic effect. The efficacy of bortezomib, a proteasome inhibitor, was validated in a time-course experiment. The cystic PDO structures were effectively prevented from maintaining their shape or expanding in size. (C) The most frequently used clinical drug combinations for CCA were used on a CCA PDO line. As shown, gemcitabine plus cisplatin had the same effect as gemcitabine alone. Similarly, in all 8 combinations tested, the overall efficacy was similar to that of the more efficacious of the 2 drugs used in combination. Scale bars: 200 μm (A) and 400 μm (B and C).