Molecular Genetics: Anton Berns

Anton Berns, Ph.D ProfessorSr.Group Leader

• +31 20 512 1991
• Anton Berns

About Anton Berns

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).