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.
| Original language | English (US) |
|---|---|
| Article number | Y |
| Journal | JCI Insight |
| Volume | 4 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jan 24 2019 |
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ASJC Scopus subject areas
- Medicine(all)
Cite this
Human primary liver cancer organoids reveal intratumor and interpatient drug response heterogeneity. / Li, Ling; Knutsdottir, Hildur; Hui, Ken; Weiss, Matthew J.; He, Jin; Philosophe, Benjamin; Cameron, Andrew M.; Wolfgang, Christopher L.; Pawlik, Timothy M.; Ghiaur, Gabriel; Ewald, Andrew J.; Mezey, Esteban; Bader, Joel S.; Selaru, Florin M.
In: JCI Insight, Vol. 4, No. 2, Y, 24.01.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Human primary liver cancer organoids reveal intratumor and interpatient drug response heterogeneity
AU - Li, Ling
AU - Knutsdottir, Hildur
AU - Hui, Ken
AU - Weiss, Matthew J.
AU - He, Jin
AU - Philosophe, Benjamin
AU - Cameron, Andrew M.
AU - Wolfgang, Christopher L.
AU - Pawlik, Timothy M.
AU - Ghiaur, Gabriel
AU - Ewald, Andrew J.
AU - Mezey, Esteban
AU - Bader, Joel S.
AU - Selaru, Florin M.
PY - 2019/1/24
Y1 - 2019/1/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85070658357&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070658357&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.121490
DO - 10.1172/jci.insight.121490
M3 - Article
C2 - 30674722
AN - SCOPUS:85070658357
VL - 4
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 2
M1 - Y
ER -