Experimental work in the Anton Berns lab stopped.
Experimental work in my lab ended in May 2019. Some of the
projects are being continued by postdocs and former colleagues. I
remain active as advisor, reviewer, and as board member of
supervisory committees and national and international organisations
dedicated to cancer research.
Research interest:
Mouse Cancer Models
The aim was to utilize genetically engineered mouse
models to define the (epi)genetic lesions involved in tumor
initiation, progression, metastasis and tumor maintenance. These
models were particularly suited to design and evaluate new
intervention strategies.
Inducible mouse models
We have made a significant investment in developing new mouse
models for a variety of tumors, using Cre/Lox mediated switching of
tumor suppressor genes and oncogenes. Both transgenesis and somatic
gene transfer are employed to express Cre recombinase and other
genes or shRNAs in a regulatable fashion. The methodology enabled
us to switch multiple oncogenes and/or tumor suppressor genes
within cells in vivo at a defined time and to monitor the relevance
of these genes for tumor initiation and progression. The induction
of highly specific tumors within a narrow time window permited us
to correlate specific genetic lesions with distinct tumor
characteristics. The general picture that transpires from these
studies is that the mouse cancer models show closer resemblance to
the human condition when they share the same mutations. By applying
sensitive in vivo imaging techniques to follow tumor growth and
metastatic spread in real time in animals we not only followed
tumor development longitudinally but also monitored response to
genetic and pharmacological interventions.
Thoracic tumors
We focused on thoracic tumors: small cell lung cancer (SCLC),
non-small cell lung cancer (NSCLC), squamous cell carcinoma (SCC)
and mesothelioma. Using different sets of conditional tumor
suppressor genes and oncogenes all the thoracic tumors can be
induced specifically. When, for example,Rbandp53are inactivated
specifically in lung, SCLC develops in nearly 100% of the mice.
These tumors closely resemble human SCLC and are often
heterogeneous consisting of different cell types, with either
neuroendocrine or mesenchymal features. Subcutaneous grafting of
each of the cell types independently gave rise to localized tumors
that retained the features of the inoculated cells. However,
grafting mixtures resulted in local growth as well as metastasis of
the neuroendocrine cells to liver indicating that the
non-neuroendocrine cells in the graft endowed the neuroendocrine
cells with metastatic potential. This shows functionality of tumor
cell heterogeneity. We try to uncover the underlying
signaling.
An important question in our studies was the role of the
cell-of-origin of these tumors. We address this by switching
oncogenes and tumor suppressor genes specifically in Clara cells,
Alveolar type II cells, neuroendocrine cells, basal epithelial
cells of lung and in the mesothelial lining of the thoracic cavity.
It appears that both the cell-of-origin and the introduced genetic
lesions are critical determinants of the phenotypic characteristics
of the resulting tumors. We are inquiring whether the cell of
origin might also explain some of the unique features of the tumor
subtypes in humans.
We were making these models more versatile by re-derivation of
ES cells from them and equipping these with DNA exchange cassettes
that allow us to swiftly introduced additional oncogenes, inducible
shRNAs or reporters in order to test their contribution to the
tumor phenotype or to the response to intervention. In this way we
could also quickly evaluate the importance of putative cancer genes
found by the sequencing DNA of human cancers. Furthermore,
transposon-based insertional mutagenesis was conducted in these
models to identify genes and pathways that strongly synergize with
the driver mutations genetically inserted in these models. This
will providfe us with clues what to look for in the cognate human
tumors.
Parallel to these experiments we developed protocols to establish
cultures from human mesothelioma and to propagate these tumors as
patient derived xenografts (PDX).
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Paul KrimpenfortAcademic Staff
