Research Report 2010 2011 - Helmholtz-Zentrum für ...

SCIENTIFIC REPORTS | Infection and Immunity | Strategies for Prevention and Therapy 105
04.4 Chronic Infection and Cancer
PROJECT LEADER | Prof. Dr. Lars Zender | Junior Research Group Chronic Infection and Cancer |
lze08@helmholtz-hzi.de
PROJECT MEMBERS | Dr. Tae-Won Kang | Dr. Michelle Stange | Dr. Torsten Wüstefeld | Dr. Tetyana Yevsa |
Daniel Dauch | Florian Heinzmann | Lisa Hönicke | Anja Hohmeyer | Nils Jedicke | Marina Pesic | Ramona Rudalska
Liver Cancer (Hepatocellular Carcinoma) represents one
of the most frequent and most deadly cancers worldwide.
The incidence of the disease is increasing, with more than
700,000 new cases per year, 50,000 of which occur in
Europe.
We are taking functional genomic approaches to study
molecular mechanisms of liver damage, liver regeneration
and liver cancer. As our major tool, we are harnessing the
naturally occurring process of RNA interference (RNAi).
Over the past couple of years we have developed and refined
microRNA based shRNA technology, which allows stable
or reversible RNAi-mediated inhibition of any endogenous
gene in cultured cells or in mouse models of liver regeneration
and liver cancer. The use of inducible RNAi allows us
to interfere with gene products within regenerating livers
or growing tumours in mice, either at a single gene level or
through pooled multi-gene screening. Genome-scale retroand
lentiviral shRNA libraries targeting the murine and
the human genome are used to conduct screens in order to
identify new therapeutic targets in regenerative medicine
and hepatobiliary oncology.
1. Translational Regenerative medicine and targeting
of liver stem cells The liver has tremendous potential
to regenerate following tissue damage caused by toxins
or infection. It is unique that differentiated hepatocytes,
which normally reside in the Go phase of the cell cycle, can
re-enter the cell cycle subsequent to liver damage and give
rise to new hepatocytes. However, when chronic liver damage
occurs, there is an exhaustion of the regenerative capacity
of hepatocytes and only partial compensation by a stem
cell compartment. The consequence is chronic liver failure,
which represents a major health problem worldwide.
We have established a unique system which allows conducting
in vivo RNAi screens to identify positive and negative
regulators of hepatocyte proliferation during chronic liver
damage. A recently completed in vivo RNAi screen identified
a dual specificity protein kinase as a promising therapeutic
target for hepatic regenerative medicine. Functional
characterization showed that knockdown of the target by
different shRNAs led to a more than 1000-fold increased
proliferative capacity of hepatocytes in a mouse model of
chronic liver damage and greatly improved survival. We
are currently working to translate the obtained genetic
information into new pharmacological strategies for hepatic
regenerative medicine.
2. Translational Oncology, mosaic cancer mouse modeling,
in vivo RNAi, identification of new, innovative
therapeutic targets in liver cancer Tumour genetics can
guide the application of particular therapeutic strategies
and can predict treatment outcome. By combining in vivo
RNAi technology with powerful mosaic liver cancer mouse
models, we have made substantial progress in pinpointing
new cancer genes and tumour suppressor networks in hepatocellular
carcinoma (HCC). In addition to probing tumour
suppressor genes in vivo one at a time, we also performed
in vivo screens to multiplex this approach. We recently performed
the first in vivo RNAi screen, which identified more
than ten new tumour suppressor genes in HCC.
Current projects in the laboratory are aiming to identify
genetic vulnerabilities in hepatobiliary malignancies. These
approaches are based on the concept of “synthetic lethality”,
which assumes that by virtue of their accumulated genetic
alterations, tumour cells may acquire vulnerabilities that
create opportunities for new therapeutic interventions.
Several high confidence targets have been identified and we
are currently trying to translate these into new treatment
strategies.
Dr. Torsten Wüstefeld (le) und Florian Heinzmann (ri) discussing
results from an experiment. On the left side: Dr. Tetyana
Yevsa, on the right side: Ramona Rudalska. Photo: HZI
Zender, L., Xue, W., Zuber, J., Semighini, C.P., Krasnitz, A., Ma, B., Zender, P., Kubicka, S.,
Luk, J.M., Schirmacher, P., McCombie, W.R., Wigler, M., Hicks, J., Hannon, G.J., Powers,
S. & Lowe, S.W. (2008) An oncogenomics-based in vivo RNAi screen identifies tumor
suppressors in liver cancer. Cell 135(5), 852-64.
Xue, W., Zender, L., Miething, C., Dickins, R.A., Hernando, E., Krizhanovsky, V.,
Cordon-Cardo, C. & Lowe, S.W. (2007) Senescence and tumour clearance is triggered by
p53 restoration in murine liver carcinomas. Nature 445(7128), 656-60.
Zender, L., Spector, M.S., Xue, W., Flemming, P., Cordon-Cardo, C., Silke, J., Fan, S.T.,
Luk, J.M., Wigler, M., Hannon, G.J., Mu, D., Lucito, R., Powers, S. & Lowe, S.W. (2007)
Identification and validation of oncogenes in liver cancer using an integrative oncogenomic
approach. Cell 125(7), 1253-67.