Analyse der Heterogenität von Tumor-initiierenden Zellen in Hepato-biliären Tumoren - Molekulare Charakterisierung und therapeutisches Abzielen auf (Krebs-)Stammzell-Eigenschaften
Zusammenfassung der Projektergebnisse
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are two major types of primary liver cancers (PLC). PLCs rank among the deadliest cancers worldwide with poor clinical outcome. Absence of clinical symptoms and effective biomarkers for early detection are main causes of late diagnosis and detrimental prognosis. Therefore, identification of potentially druggable targets and subsequent development of next-generation targeted therapies, as well as translation of these findings into clinical practice remain crucial. To further govern translational advancements, development of primary culture models that closely recapitulate phenotypic and molecular diversities as well as the cell of origin, i.e. putative cancer stem cell (CSC), of PLC is urgently needed in order to support a translation from laboratory studies to the bedside and improve patient outcome. Major obstacle still represents a lack of models that truly and accurately represent morphological and molecular heterogeneity of original tumors. As an integral part of the here presented project, we report successful establishment and detailed characterization novel patient-derived primary liver cancer cell lines (PPCL) from HCC and intrahepatic CCA. The model was subsequently utilized to address and modulate important aspects of CSC biology in PLC. Morphologic and phenotypic characteristics of newly established cell lines were compared to original tumors and confirmed a high level of similarity. Tumor grading and genomic stability were further assessed to determine background setting for successful PPCL establishment. Our results provide evidence that less differentiated tumors with higher genomic instability possess a higher likelihood of successful PPCL establishment. Time course analyses of selected CSCs markers as well as transcriptomic and genomic changes were performed using FACS as well as nextgeneration sequencing (NGS) to characterize and generate molecular profiles of newly derived PPCL and investigate how accurately they recapitulate original cancer tissue. Analyses confirmed that PPCL retain similar profile as corresponding primary tumors during long-term culturing. Key oncogenic alterations were identified by targeted NGS (e.g. TP53, KRAS, CTNNB1, MET) and cell lines carrying potentially actionable mutations were treated with corresponding specific inhibitors. Overall, our integrative analyses demonstrate that PPCLs represent refined model for discovery of relevant molecular subgroups and exploration of precision medicine approaches for the treatment of primary liver cancer and modulation of putative CSCs.
Projektbezogene Publikationen (Auswahl)
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Curcumin Effectively Depletes Hepatic Cancer Stem- Like Cells by NF-kB Mediated Inhibition of Histone Deacetylases. J. Hepatol. 2015 Sep;63(3):661-9
Marquardt JU., Gomez-Quiroz L., Arreguin Camacho LO., Pinna F., Lee YH., Kitade M., Palestino Domínguez M., Breuhahn K., Conner EA., Galle PR., Andersen JB., Factor VM., Thorgeirsson SS.
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Functional and Genetic Deconstruction of the Cellular Origin in Liver Cancer. Nat Rev Cancer 2015 Oct 23;15(11):653-67
Marquardt JU., Andersen JB., Thorgeirsson SS.
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Increased liver carcinogenesis, and enrichment of stem cell properties in livers of Dickkopf 2 (Dkk2) deleted mice. Oncotarget. 2016 May 17;7(20):28903-13
Maass T., Marquardt JU., Lee JS., Krupp M., Scholz-Kreisel P., Mogler C., Schirmacher P., Müller M., Westphal H., Galle PR., Teufel A.
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Oncogenic driver genes and the inflammatory microenvironment dictate liver tumor phenotype. Hepatology 2016 Feb 4
Matter MS., Marquardt JU., Andersen JB., Korokhov N., Stauffer JK., Kaji K., Decaens T., Quintavalle C., Quagliata L., Elloumi F., Hoang F., Hansen K., Molinolo A., Conner EA., Factor VM., Thorgeirsson SS.
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Adverse genomic alterations and stemness features are induced by field cancerization in the microenvironment of hepatocellular carcinomas. Oncotarget. 2017 Jul 25;8(30):48688-48700
Castven C., Fischer M., Becker D., Heinrich S., Andersen JB., Strand D., Sprinzl MF., Strand S., Czauderna C., Heilmann S., Roessler S., Weinmann A., Wörns MA., Thorgeirsson SS., Galle PR., Matter MS., Lang H., Marquardt JU.
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Induction of chromosomal instability (CIN) by cooperative activation of yes-associated protein (YAP) and FOXM1 in hepatocarcinogenesis. Gastroenterology. 2017 Jun;152(8):2037-2051
Weiler S., Pinna F., Wolf T., Lutz T., Geldiyev S., Wan S., Knaub M., Rössler R., Becker D., Sticht C., Gretz N., Lang H., Ustiyan V., Singer S., Lee JS., Marquardt JU., Schirmacher P., Kalinichenko V., Breuhahn K.
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Mislocalization of the cell polarity protein Scribble (Scrib) induces SPARC secretion in hepatocellular carcinoma. Hepatology 2017 Nov 20
Wan S., Meyer AS., Weiler SM., Rupp C., Sticht C., Singer S., Tóth M., Thomann S., Roessler S., Schorpp-Kistner M., Schmitt J., Gretz N., Angel P., Tschaharganeh D., Marquardt JU., Schirmacher P., Pinna F., Breuhahn K.
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Immunotherapy of Hepatocellular Carcinoma. Oncol Res Treat. 2018;41(5):292-297
Heinrich B., Czauderna C., Marquardt JU.
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The role of TGFβ in human hepatocarcinogenesis: mechanistic and therapeutic implications from an integrative multi-omics approach. Gastroenterology 2018 Jan;154(1):17-20
Marquardt JU.
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Application of patient-derived liver cancer cells for phenotypic characterization and therapeutic target identification. Int J Cancer. 2019 Jun 1;144(11):2782-2794
Castven D., Becker D., Czauderna C., Wilhelm D., Andersen JB., Strand S., Hartmann M., Heilmann-Heimbach S., Roth W,, Hartmann N., Straub BK., Mahn FL., Franck S., Pereira S., Haupts A., Vogel A., Wörns MA., Weinmann A,, Heinrich S., Lang H., Thorgeirsson SS., Galle PR., Marquardt JU.
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Context-Dependent Role of NF-κB Signaling in Primary Liver Cancer-from Tumor Development to Therapeutic Implications. Cancers (Basel). 2019 Jul 25;11(8)
Czauderna C, Castven D, Mahn FL, Marquardt JU
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Dynamics and predicted drug response of a gene network linking dedifferentiation with beta-catenin dysfunction in hepatocellular carcinoma. J Hepatol. 2019 Apr 3
Gérard C., Di-Luoffo M., Gonay L., Caruso S, Couchy G., Loriot A., Castven D., Tao J., Konobrocka K., Cordi S., Monga SP., Hanert E., Marquardt JU, Zucman-Rossi J., Lemaigre FP
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Predisposition to Apoptosis in Hepatocellular Carcinoma: From Mechanistic Insights to Therapeutic Strategies. Front Oncol. 2019 Dec 13;9:1421
Marquardt JU., Edlich F.
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The mitochondrial type I topoisomerase TOP1MT promotes mitochondrial translation and carcinogenesis. Nat. Commun. 2019 Jan 8;10(1):83
Baechler SA., Factor VM., Dalla Rosa I., Ravji A., Becker D., Khiati S., Miller Jenkins LM., Lang M., Huang SY., Sourbier C., Neckers LM., Zhang HL., Spinazzola A., Huang SN., Marquardt JU., Pommier Y.
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YAP-dependent induction of UHMK1 supports cell proliferation and YAP target gene expression through the oncogene MYBL2. Oncogene 2019 Apr 1
Wie T., Weiler S., Tóth M., Sticht C., Lutz T., Thomann S., De La Torre C., Straub B., Merker S., Ruppert S., Marquardt JU., Singer S., Gretz N., Schirmacher P., Breuhahn K.
