Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer

Beatrice Bissig-Choisat, Claudia Kettlun-Leyton, Xavier D. Legras, Barry Zorman, Mercedes Barzi, Leon L. Chen, Mansi D. Amin, Yung Hsin Huang, Robia G. Pautler, Oliver A. Hampton, Masand M. Prakash, Diane Yang, Malgorzata Borowiak, Donna Muzny, Harsha Vardhan Doddapaneni, Jianhong Hu, Yan Shi, M. Waleed Gaber, M. John Hicks, Patrick A. ThompsonYiling Lu, Gordon Mills, Milton Finegold, John A. Goss, D. Williams Parsons, Sanjeev A. Vasudevan, Pavel Sumazin, Dolores López-Terrada, Karl Dimiter Bissig

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)325-333
Number of pages9
JournalJournal of Hepatology
Volume65
Issue number2
DOIs
StatePublished - Aug 1 2016
Externally publishedYes

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Liver Neoplasms
Heterografts
Pediatrics
Cell Line
Neoplasms
Therapeutics
Animal Models
Rare Diseases
RNA Sequence Analysis
Hepatoblastoma
Investigational Therapies
Poisons
Gene Expression Profiling
Phosphatidylinositol 3-Kinases
Transcriptome
Stem Cells

Keywords

  • Patient-derived xenograft
  • Pediatric liver cancer
  • Therapeutic testing

ASJC Scopus subject areas

  • Hepatology

Cite this

Bissig-Choisat, B., Kettlun-Leyton, C., Legras, X. D., Zorman, B., Barzi, M., Chen, L. L., ... Bissig, K. D. (2016). Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer. Journal of Hepatology, 65(2), 325-333. https://doi.org/10.1016/j.jhep.2016.04.009

Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer. / Bissig-Choisat, Beatrice; Kettlun-Leyton, Claudia; Legras, Xavier D.; Zorman, Barry; Barzi, Mercedes; Chen, Leon L.; Amin, Mansi D.; Huang, Yung Hsin; Pautler, Robia G.; Hampton, Oliver A.; Prakash, Masand M.; Yang, Diane; Borowiak, Malgorzata; Muzny, Donna; Doddapaneni, Harsha Vardhan; Hu, Jianhong; Shi, Yan; Gaber, M. Waleed; Hicks, M. John; Thompson, Patrick A.; Lu, Yiling; Mills, Gordon; Finegold, Milton; Goss, John A.; Parsons, D. Williams; Vasudevan, Sanjeev A.; Sumazin, Pavel; López-Terrada, Dolores; Bissig, Karl Dimiter.

In: Journal of Hepatology, Vol. 65, No. 2, 01.08.2016, p. 325-333.

Research output: Contribution to journalArticle

Bissig-Choisat, B, Kettlun-Leyton, C, Legras, XD, Zorman, B, Barzi, M, Chen, LL, Amin, MD, Huang, YH, Pautler, RG, Hampton, OA, Prakash, MM, Yang, D, Borowiak, M, Muzny, D, Doddapaneni, HV, Hu, J, Shi, Y, Gaber, MW, Hicks, MJ, Thompson, PA, Lu, Y, Mills, G, Finegold, M, Goss, JA, Parsons, DW, Vasudevan, SA, Sumazin, P, López-Terrada, D & Bissig, KD 2016, 'Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer', Journal of Hepatology, vol. 65, no. 2, pp. 325-333. https://doi.org/10.1016/j.jhep.2016.04.009
Bissig-Choisat B, Kettlun-Leyton C, Legras XD, Zorman B, Barzi M, Chen LL et al. Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer. Journal of Hepatology. 2016 Aug 1;65(2):325-333. https://doi.org/10.1016/j.jhep.2016.04.009
Bissig-Choisat, Beatrice ; Kettlun-Leyton, Claudia ; Legras, Xavier D. ; Zorman, Barry ; Barzi, Mercedes ; Chen, Leon L. ; Amin, Mansi D. ; Huang, Yung Hsin ; Pautler, Robia G. ; Hampton, Oliver A. ; Prakash, Masand M. ; Yang, Diane ; Borowiak, Malgorzata ; Muzny, Donna ; Doddapaneni, Harsha Vardhan ; Hu, Jianhong ; Shi, Yan ; Gaber, M. Waleed ; Hicks, M. John ; Thompson, Patrick A. ; Lu, Yiling ; Mills, Gordon ; Finegold, Milton ; Goss, John A. ; Parsons, D. Williams ; Vasudevan, Sanjeev A. ; Sumazin, Pavel ; López-Terrada, Dolores ; Bissig, Karl Dimiter. / Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer. In: Journal of Hepatology. 2016 ; Vol. 65, No. 2. pp. 325-333.
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abstract = "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.",
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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

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

PY - 2016/8/1

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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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