Establishment of a hepatocellular carcinoma patient‐derived xenograft platform and its application in biomarker identification

Abstract

Using a method optimized in hepatocellular carcinoma (HCC), we established patient‐derived xenograft (PDX) models with an increased take rate (42.2%) and demonstrated that FBS +10% dimethyl sulfoxide exhibited the highest tumor take rate efficacy. Among 254 HCC patients, 103 stably transplantable xenograft lines that could be serially passaged, cryopreserved and revived were established. These lines maintained the diversity of HCC and the essential features of the original specimens at the histological, transcriptome, proteomic and genomic levels. Tumor engraftment was associated with lack of encapsulation, poor tumor differentiation, large size and overexpression of cancer stem cell biomarkers, and was an independent predictor for overall survival and tumor recurrence after resection. To confirm the preclinical value of the PDX model in HCC treatment, several antitumor agents were tested in 16 selected PDX models. The results revealed a high degree of pharmacologic heterogeneity in the cohort, as well as heterogeneity to different agents in the same individual. The sorafenib responses observed between HCC patients and the corresponding PDXs were also consistent. After molecular characterization of the PDX models, we explored the predictive markers for sorafenib response and found that mitogen‐activated protein kinase kinase kinase 1 (MAP3K1) might play an important role in sorafenib resistance and sorafenib response is impaired in patients with MAP3K1 downexpression. Our results indicated that PDX models could accurately reproduce patient tumors biology and could aid in the discovery of new treatments to advance in precision medicine.

The Essential Factors of Establishing Patient-derived Tumor Model

“…[16]. Moreover, these hepatocellular carcinoma sample removed from patients with large size tumor (>5cm) have higher PDX establishment rate (87/130, 67%) compare with small size (≤5cm) (16/124, 12.9%) [17]. Similarly, Jung et al successfully produced 20 PDXs of pancreatic cancer, they found that tumor size is a significant factor of the success of PDX [18].…”

Anlotinib suppresses tumor progression via blocking the VEGFR2/PI3K/AKT cascade in intrahepatic cholangiocarcinoma

“…PDX models were constructed as described in our previous study 39 . Six ICC cases with successful construction were resuscitated and implanted under the skin of nonobese diabetic-severe combined immunodeficiency mice.…”

“…Eighteen days after drug intervention, the mice were sacrificed using dislocation, and the tumor tissues were harvested to measure tumor weights and volumes. Tumor size was measured using a caliper, and tumor volume was calculated using: tumor volume = 0.5 × length × (width) 2 as we previously described 39 . The antitumor effect of anlotinib was evaluated using TGI.…”

Deciphering Tumor Heterogeneity in Hepatocellular Carcinoma (HCC)—Multi-Omic and Singulomic Approaches

“…While such approaches have been successful in other cancers in combination with other technologies like exome sequencing, 58,59 establishing PDXs in HCC is challenging since the rate of engraftment is traditionally considered to be low. 55…”