TY - JOUR
T1 - Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer
AU - Bissig-Choisat, Beatrice
AU - Kettlun-Leyton, Claudia
AU - Legras, Xavier D.
AU - Zorman, Barry
AU - Barzi, Mercedes
AU - Chen, Leon L.
AU - Amin, Mansi D.
AU - Huang, Yung Hsin
AU - Pautler, Robia G.
AU - Hampton, Oliver A.
AU - Prakash, Masand M.
AU - Yang, Diane
AU - Borowiak, Malgorzata
AU - Muzny, Donna
AU - Doddapaneni, Harsha Vardhan
AU - Hu, Jianhong
AU - Shi, Yan
AU - Gaber, M. Waleed
AU - Hicks, M. John
AU - Thompson, Patrick A.
AU - Lu, Yiling
AU - Mills, Gordon B.
AU - Finegold, Milton
AU - Goss, John A.
AU - Parsons, D. Williams
AU - Vasudevan, Sanjeev A.
AU - Sumazin, Pavel
AU - López-Terrada, Dolores
AU - Bissig, Karl Dimiter
N1 - Funding Information:
K.D.B. is supported by the Texas Hepatocellular Carcinoma Consortium (THCCC) (CPRIT #RP150587) and the Diana Helis Henry and Adrienne Helis Malvin Medical Research Foundations. B.B.C. was supported by 5T32HL092332-13, L.L.C by T32-DK07664, W.D.P by NHGRI/NCI 1U01HG006485 and the Sidney Kimmel Foundation for Cancer Research. D.W.P. and D.L.T. by the Cancer Prevention & Research Institute of Texas (CPRIT RP101195 and RP120715). The DLDCC is supported by P30CA125123. CMM core facility of Texas Medical Center Digestive Disease Center (P30-DK56338).
Publisher Copyright:
© 2016 European Association for the Study of the Liver
PY - 2016/8/1
Y1 - 2016/8/1
N2 - Background & Aims 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. Methods 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. Results 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. Conclusions 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. Lay summary 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.
AB - Background & Aims 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. Methods 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. Results 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. Conclusions 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. Lay summary 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.
KW - Patient-derived xenograft
KW - Pediatric liver cancer
KW - Therapeutic testing
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U2 - 10.1016/j.jhep.2016.04.009
DO - 10.1016/j.jhep.2016.04.009
M3 - Article
C2 - 27117591
AN - SCOPUS:84969645459
SN - 0168-8278
VL - 65
SP - 325
EP - 333
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 2
ER -