Application of patient-derived liver cancer cells for phenotypic characterization and therapeutic target identification

TY - JOUR

T1 - Application of patient-derived liver cancer cells for phenotypic characterization and therapeutic target identification

AU - Castven, Darko

AU - Becker, Diana

AU - Czauderna, Carolin

AU - Wilhelm, Diana

AU - Andersen, Jesper B

AU - Strand, Susanne

AU - Hartmann, Monika

AU - Heilmann-Heimbach, Stefanie

AU - Roth, Wilfried

AU - Hartmann, Nils

AU - Straub, Beate K

AU - Mahn, Friederike L

AU - Franck, Sophia

AU - Pereira, Sharon

AU - Haupts, Anna

AU - Vogel, Arndt

AU - Wörns, Marcus A

AU - Weinmann, Arndt

AU - Heinrich, Stefan

AU - Lang, Hauke

AU - Thorgeirsson, Snorri S

AU - Galle, Peter R

AU - Marquardt, Jens U

N1 - This article is protected by copyright. All rights reserved.

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Primary liver cancer (PLC) ranks among the most lethal solid cancers worldwide due to lack of effective biomarkers for early detection and limited treatment options in advanced stages. Development of primary culture models that closely recapitulate phenotypic and molecular diversities of PLC is urgently needed to improve the patient outcome. Long-term cultures of 7 primary liver cancer cell lines of hepatocellular and cholangiocellular origin were established using defined culture conditions. Morphological and histological characteristics of obtained cell lines and xenograft tumors were analyzed and compared to original tumors. Time course analyses of transcriptomic and genomic changes were performed using next-generation sequencing (NGS). Key oncogenic alterations were identified by targeted NGS and cell lines carrying potentially actionable mutations were treated with corresponding specific inhibitors. PDCL fully resembled morphological features of the primary cancers in vitro and in vivo over extended period in culture. Genomic alterations as well as transcriptome profiles showed high similarity with primary tumors and remained stable during long-term culturing. Targeted-NGS confirmed that key oncogenic mutations such as TP53, KRAS, CTNNB1 as well as actionable mutations (e.g. MET, cKIT, KDR) were highly conserved in PDCL and amenable for individualized therapeutic approaches. Integrative genomic and transcriptomic approaches further demonstrated that PDCL more closely resemble molecular and prognostic features of PLC than established cell lines and are valuable tool for direct target evaluation. Our integrative analysis demonstrates that PDCL represents refined model for discovery of relevant molecular subgroups and exploration of precision medicine approaches for the treatment of this deadly disease.

AB - Primary liver cancer (PLC) ranks among the most lethal solid cancers worldwide due to lack of effective biomarkers for early detection and limited treatment options in advanced stages. Development of primary culture models that closely recapitulate phenotypic and molecular diversities of PLC is urgently needed to improve the patient outcome. Long-term cultures of 7 primary liver cancer cell lines of hepatocellular and cholangiocellular origin were established using defined culture conditions. Morphological and histological characteristics of obtained cell lines and xenograft tumors were analyzed and compared to original tumors. Time course analyses of transcriptomic and genomic changes were performed using next-generation sequencing (NGS). Key oncogenic alterations were identified by targeted NGS and cell lines carrying potentially actionable mutations were treated with corresponding specific inhibitors. PDCL fully resembled morphological features of the primary cancers in vitro and in vivo over extended period in culture. Genomic alterations as well as transcriptome profiles showed high similarity with primary tumors and remained stable during long-term culturing. Targeted-NGS confirmed that key oncogenic mutations such as TP53, KRAS, CTNNB1 as well as actionable mutations (e.g. MET, cKIT, KDR) were highly conserved in PDCL and amenable for individualized therapeutic approaches. Integrative genomic and transcriptomic approaches further demonstrated that PDCL more closely resemble molecular and prognostic features of PLC than established cell lines and are valuable tool for direct target evaluation. Our integrative analysis demonstrates that PDCL represents refined model for discovery of relevant molecular subgroups and exploration of precision medicine approaches for the treatment of this deadly disease.

U2 - 10.1002/ijc.32026

DO - 10.1002/ijc.32026

M3 - Journal article

C2 - 30485423

SN - 0898-6924

VL - 144

SP - 2782

EP - 2794

JO - International Journal of Cancer

JF - International Journal of Cancer

IS - 11

ER -