Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer.
Pediatric liver cancer is a rare but serious disease whose incidence is rising, and for which the therapeutic options are limited. Development of more targeted, less toxic therapies is hindered by the lack of an experimental animal model that captures the heterogeneity and metastatic capability of these tumors.



Here we established an orthotopic engraftment technique to model a series of patient-derived tumor xenograft (PDTX) from pediatric liver cancers of all major histologic subtypes: hepatoblastoma, hepatocellular cancer and hepatocellular malignant neoplasm. We utilized standard (immuno) staining methods for histological characterization, RNA sequencing for gene expression profiling and genome sequencing for identification of druggable targets. We also adapted stem cell culturing techniques to derive two new pediatric cancer cell lines from the xenografted mice.



The patient-derived tumor xenografts recapitulated the histologic, genetic, and biological characteristics-including the metastatic behavior-of the corresponding primary tumors. Furthermore, the gene expression profiles of the two new liver cancer cell lines closely resemble those of the primary tumors. Targeted therapy of PDTX from an aggressive hepatocellular malignant neoplasm with the MEK1 inhibitor trametinib and pan-class I PI3 kinase inhibitor NVP-BKM120 resulted in significant growth inhibition, thus confirming this PDTX model as a valuable tool to study tumor biology and patient-specific therapeutic responses.



The novel metastatic xenograft model and the isogenic xenograft-derived cell lines described in this study provide reliable tools for developing mutation- and patient-specific therapies for pediatric liver cancer.



Pediatric liver cancer is a rare but serious disease and no experimental animal model currently captures the complexity and metastatic capability of these tumors. We have established a novel animal model using human tumor tissue that recapitulates the genetic and biological characteristics of this cancer. We demonstrate that our patient-derived animal model, as well as two new cell lines, are useful tools for experimental therapies.
Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Beatrice
B
Bissig-Choisat
Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Claudia
C
Kettlun-Leyton
Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Xavier D
XD
Legras
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Barry
B
Zorman
Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Mercedes
M
Barzi
Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Leon L
LL
Chen
Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Mansi D
MD
Amin
Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA.
Yung-Hsin
YH
Huang
Small Animal Imaging Facility, Texas Children's Hospital, Houston, TX, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
Robia G
RG
Pautler
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
Oliver A
OA
Hampton
Department of Pediatric Radiology, Texas Children's Hospital, Houston, TX, USA.
Masand M
MM
Prakash
Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA; Graduate Program Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Diane
D
Yang
Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA; Graduate Program Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX, USA; McNair Medical Institute, Houston, USA.
Malgorzata
M
Borowiak
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
Donna
D
Muzny
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
Harsha Vardhan
HV
Doddapaneni
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
Jianhong
J
Hu
Michael E. DeBakey Department of Surgery, Division of Abdominal Transplantation and Division of Hepatobiliary Surgery, Baylor College of Medicine, Houston, TX, USA; Department of Surgery, Texas Children's Hospital, Houston, TX, USA.
Yan
Y
Shi
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Small Animal Imaging Facility, Texas Children's Hospital, Houston, TX, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
M Waleed
MW
Gaber
Department of Pathology, Texas Children's Hospital, Houston, TX, USA.
M John
MJ
Hicks
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Patrick A
PA
Thompson
Department of Systems Biology, MD Anderson Cancer Center, Houston, TX, USA.
Yiling
Y
Lu
Department of Systems Biology, MD Anderson Cancer Center, Houston, TX, USA.
Gordon B
GB
Mills
Department of Pathology, Texas Children's Hospital, Houston, TX, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
Milton
M
Finegold
Michael E. DeBakey Department of Surgery, Division of Abdominal Transplantation and Division of Hepatobiliary Surgery, Baylor College of Medicine, Houston, TX, USA; Department of Surgery, Texas Children's Hospital, Houston, TX, USA.
John A
JA
Goss
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
D Williams
DW
Parsons
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA; Michael E. DeBakey Department of Surgery, Division of Abdominal Transplantation and Division of Hepatobiliary Surgery, Baylor College of Medicine, Houston, TX, USA; Department of Surgery, Texas Children's Hospital, Houston, TX, USA.
Sanjeev A
SA
Vasudevan
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
Pavel
P
Sumazin
Department of Pathology, Texas Children's Hospital, Houston, TX, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
Dolores
D
López-Terrada
Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA; Graduate Program Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX, USA. Electronic address: bissig@bcm.edu.
Karl-Dimiter
KD
Bissig
D000818:Animals; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D002648:Child; D004195:Disease Models, Animal; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms; D051379:Mice; D009368:Neoplasm Transplantation; D023041:Xenograft Model Antitumor Assays
Patient-derived xenograft; Pediatric liver cancer; Therapeutic testing