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Generation of matched patient-derived xenograft in vitro-in vivo models using 3D macroporous hydrogels for the study of liver cancer. (Biomaterials, Jan 2018)

Fong ELS1, Toh TB2, Lin QXX2, Liu Z3, Hooi L2, Mohd Abdul Rashid MB2, Benoukraf T2, Chow EK4, Huynh TH5, Yu H6.

1 Department of Biomedical Engineering, National University of Singapore, Singapore.
2 Cancer Science Institute of Singapore, National University of Singapore, Singapore.
3 Institute of Bioengineering and Nanotechnology, Agency for Science, Technology and Research (A*STAR), Singapore.
4 Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
5 National Cancer Center Singapore, Singapore.
6 Institute of Bioengineering and Nanotechnology, Agency for Science, Technology and Research (A*STAR), Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Mechanobiology Institute, National University of Singapore, Singapore; BioSyM, Singapore-MIT Alliance for Research and Technology, Singapore; Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China; NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore, Singapore

Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide, often manifesting at the advanced stage when cure is no longer possible. The discrepancy between preclinical findings and clinical outcome in HCC is well-recognized. So far, sorafenib is the only targeted therapy approved as first-line therapy for patients with advanced HCC. There is an urgent need for improved preclinical models for the development of HCC-targeted therapies. Patient-derived xenograft (PDX) tumor models have been shown to closely recapitulate human tumor biology and predict patient drug response. However, the use of PDX models is currently limited by high costs and low throughput. In this study, we engineered in vitro conditions conducive for the culture of HCC-PDX organoids derived from a panel of 14 different HCC-PDX lines through the use of a three-dimensional macroporous cellulosic sponge system. To validate the in vitro HCC-PDX models, both in vivo and in vitro HCC-PDX models were subjected to whole exome sequencing and RNA-sequencing. Correlative studies indicate strong concordance in genomic and transcriptomic profiles as well as intra-tumoral heterogeneity between each matched in vitro-in vivo HCC-PDX pairs. Furthermore, we demonstrate the feasibility of using these in vitro HCC-PDX models for drug testing, paving the way for more efficient preclinical studies in HCC drug development.

KEYWORDS: 3D tumor model; Drug testing; Hepatocellular carcinoma; Organoids; Patient-derived xenograft

PMID: 29353739