Plastizität von kombiniert hepatozellulär-cholangiozellulären Karzinomen
Zusammenfassung der Projektergebnisse
Primary liver cancer includes three main types of carcinoma: hepatocellular carcinoma, cholangiocellular carcinoma (CCA), and mixed hepatocellular‐cholangiocellular carcinoma (HCC‐CCA). HCC‐CCA comprises a heterogeneous group of tumors that show areas of both hepatocellular and cholangiocellular differentiation suggesting that both tumor components may be derived from a single cell of origin. In line with this, lineage tracing experiments in mice showed that CCA may develop from hepatocytes suggesting plasticity as the underlying mechanism. This project aimed at the identification of genes determining the type of primary liver cancer. Therefore, tumor samples of human HCC‐CCA were subjected to a sequencing technology allowing for mutation analysis of all genes and profiling of gene expression. From these data, genes showing either a component‐specific mutation or an up‐ or downregulation of gene expression in only one component of the tumor were identified. The selected candidate genes were then analyzed in murine models of HCC and CCA, which were generated by a special technique called hydrodynamic tail vein injection of transposon vectors. The candidate genes, which possess the potential to alter the tumor type of murine liver cancer, were identified by microscopy of tumor samples and subsequent sequencing of positively evaluated samples to identify the individual gene‐of‐interest. From sequencing of human tumor samples, 54 genes were considered as candidate genes affecting the tumor type. 24 genes were derived from exome sequencing and 30 candidates were derived from RNA sequencing. Preventing the regular gene expression of these genes in murine liver cancer models validated that the loss‐of‐function of six genes altered the appearance of liver cancer. These six genes were then validated independently. Therefore, each alteration observed in the human tumor tissue was tested in the murine liver cancer models leading to validation of two candidate genes (FOSL1, ASB15). Functional analyses in cell culture showed that FOSL1 increases the invasive properties of liver cancer cells, which involves the activation of other non‐neoplastic cell types in the tumor stroma. A similar effect was observed following ASB15 expression, which additionally also increased the proliferation of tumor cells and their ability to form new tumor cell colonies. Interestingly, this is the first‐time that a functional role of ASB15 has been reported in epithelial cells. This gene has also not been implicated in tumor development before. To some extent related to the COVID19 pandemics the project got delayed and thus further mechanistical characterization is still ongoing. In case, this may identify a new mechanism amenable to drug treatment the further potential regarding development of a new treatment strategy for liver cancer will be exploited.
Projektbezogene Publikationen (Auswahl)
- (2018) Necroptosis microenvironment directs lineage commitment in liver cancer. Nature 562:69‐75
Seehawer M, Heinzmann F, D'Artista L, Harbig J, Roux PF, Hoenicke L, Dang H, Klotz S, Robinson L, Doré G, Rozenblum N, Kang TW, Chawla R, Buch T, Vucur M, Roth M, Zuber J, Luedde T, Sipos B, Longerich T, Heikenwälder M, Wang XW, Bischof O, Zender L
(Siehe online unter https://doi.org/10.1038/s41586-018-0519-y) - (2019) RSPO2 gene rearrangement: a powerful driver of β‐catenin activation in liver tumours. Gut 68:1287‐1296
Longerich T, Endris V, Neumann O, Rempel E, Kirchner M, Abadi Z, Uhrig S, Kriegsmann M, Weiss KH, Breuhahn K, Mehrabi A, Weber TF, Wilkens L, Straub BK, Rosenwald A, Schulze F, Brors B, Froehling S, Pellegrino R, Budczies J, Schirmacher P, Stenzinger A
(Siehe online unter https://doi.org/10.1136/gutjnl-2018-317632) - (2021) Combined CD40 Agonist and Anti‐PD1 Impairs Tumor Growth in Murine Intrahepatic Cholangiocarcinoma. J Hepatol 74:1145‐1154
Diggs LP, Ma C, Heinrich B, Ruf B, Cui L, Zhang Q, McVey JC, Wabitsch S, Heinrich H, Longerich T, Loosen SH, Luedde T, Neumann U, Desar S, Kleiner D, Gores G, Rosato U, Lai L, Subramanyam V, Wang XW, Greten TF
(Siehe online unter https://doi.org/10.1016/j.jhep.2020.11.037) - (2021) Gut microbiome directs hepatocytes to recruit MDSC and promote cholangiocarcinoma. Cancer Discov 11:1248‐1267
Zhang Q, Ma C, Duan Y, Heinrich B, Rosato U, Diggs L, Ma L, Roy S, Fu Q, Brown Z, Wabitsch S, Thovarai V, Fu J, Feng D, Ruf B, Cui L, Subramanyam V, Frank K, Wang S, Kleiner D, Ritz T, Rupp C, Gao B, Longerich T, Kroemer A, Wang XW, Ruchirawat M, Korangy F, Schnabl B, Trinchieri G, Greten TF
(Siehe online unter https://doi.org/10.1158/2159-8290.cd-20-0304) - (2021). Serum Response Factor (SRF) Drives the Transcriptional Upregulation of the MDM4 Oncogene in HCC. Cancers (Basel) 13:199
Pellegrino R, Thavamani A, Calvisi DF, Budczies J, Neumann A, Geffers R, Kroemer J, Greule D, Schirmacher P, Nordheim A, Longerich T
(Siehe online unter https://doi.org/10.3390/cancers13020199) - (2022) Identification and validation of a plasticity driver of combined hepatocellular‐cholangiocarcinoma using functional interspecies comparison. Z Gastroenterol 60:36
Ganjian N, Abadi Z, Trompak O, Geffers R, Zender L, Pellegrino R. Longerich T
(Siehe online unter https://doi.org/10.1055/s-0041-1740768)
