Datasets describing the growth and molecular features of hepatocellular carcinoma patient-derived xenograft cells grown in a three-dimensional macroporous hydrogel.

This data article presents datasets associated with the research article entitled "Generation of matched patient-derived xenograft in vitro-in vivo models using 3D macroporous hydrogels for the study of liver cancer" (Fong et al., 2018) [1]. A three-dimensional macroporous sponge system was used to generate in vitro counterparts to various hepatocellular carcinoma patient-derived xenograft (HCC-PDX) lines. This article describes the viability, proliferative capacity and molecular features (genomic and transcriptomic profiles) of the cultured HCC-PDX cells. The sequencing datasets are made publicly available to enable critical or further analyzes.

Generation of matched patient-derived xenograft in vitro-in vivo models using 3D macroporous hydrogels for the study of liver cancer.

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.

Mitochondrial-Targeting MET Kinase Inhibitor Kills Erlotinib-Resistant Lung Cancer Cells.

Lung cancer cells harboring activating EGFR mutations acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) by activating several bypass mechanisms, including MET amplification and overexpression. We show that a significant proportion of activated MET protein in EGFR TKI-resistant HCC827 lung cancer cells resides within the mitochondria. Targeting the total complement of MET in the plasma membrane and mitochondria should render these cells more susceptible to cell death and hence provide a means of circumventing drug resistance. Herein, the mitochondrial targeting triphenylphosphonium (TPP) moiety was introduced to the selective MET kinase inhibitor PHA665752. The resulting TPP analogue rapidly localized to the mitochondria of MET-overexpressing erlotinib-resistant HCC827 cells, partially suppressed the phosphorylation (Y1234/Y1235) of MET in the mitochondrial inner membrane and was as cytotoxic and apoptogenic as the parent compound. These findings provide support for the targeting of mitochondrial MET with a TPP-TKI conjugate as a means of restoring responsiveness to chemotherapy.