Research interest
Mouse Cancer Models
The aim is to utilize genetically engineered mouse models
to define the (epi)genetic lesions involved in tumor initiation,
progression, metastasis and tumor maintenance. These models are
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 enables 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 permits 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 can follow tumor development longitudinally but also
monitor response to genetic and pharmacological
interventions.
Thoracic tumors
We focus 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 is 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 are 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
can also quickly evaluate the importance of putative cancer genes
found by the sequencing DNA of human cancers. Furthermore,
transposon-based insertional mutagenesis is 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 are developing protocols to
establish cultures from human mesothelioma and to propagate these
tumors as patient derived xenografts (PDX).
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Paul KrimpenfortAcademic Staff
Jitendra Badhai,Ph.DPostdoctoral Fellow
Lorenzo Bombardelli, Ph.DPostdoctoral Fellow
Guistina Ferone, Ph.DPostdoctoral fellow
Miranda CozijnsenTechnician
