The ambition of the VIB Center for Cancer Biology (CCB) is to contribute to a better understanding of the biology that underlies cancer initiation, progression and metastatic dissemination with the ultimate goal to develop more effective and specific anti-cancer (combination) therapies.
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Laboratory for Mechanisms of Cell Transformation
Our research interests are focused on understanding the cooperative interactions that conspire to promote tumorigenic transformation. To discover drivers of cancer development and progression, we create experimental models of cell transformation derived from primary human cells that mimic alterations found in human cancer samples. These models provide a useful platform to delineate pathways involved in cell transformation and to discover new targets for therapeutic intervention. In particular, we are pursuing two research directions:
• Post-translational modification of the RAS-like GTPase
Ras and Rap proteins are closely related small GTPases. Whereas Ras is known for its role in cell proliferation and survival, Rap1 is predominantly involved in cell adhesion and cell junction formation. Ras is the most common oncogene in human cancer - mutations that permanently activate Ras are found in about 25% of all human tumors. On the other hand, activation of Rap1 is known to contribute to tumor metastasis.
We and others recently found that members of the Ras family undergo reversible ubiquitination. We revealed that ubiquitination of the RalB GTPases provides the switch for the dual functions of RalB in autophagy and innate immune response. On the other hand, K-Ras ubiquitination dramatically affects its tumorigenic properties. This strongly underlines the importance of reversible ubiquitination in regulation of the Ras-like GTPases. We are exploring how reversible ubiquitination of the Ras-like GTPase is regulated and how ubiquitination of Ras and Rap1 GTPases contributes to cancer development and progression.
• The role of large chromosomal deletions in cancer development and progression
Somatically acquired chromosomal deletions are extremely common in cancer, in a typical cancer sample, 25% of the genome is affected by chromosome arm-level deletions. Chromosomal deletions may occur over recessive cancer genes, miRNA clusters and/or regulatory regions, where they can confer selective growth advantage. However, a large size of chromosomal deletions makes it difficult to determine the target. As well, some chromosomal deletions may not confer any clonal growth advantage but may occur in regions with a higher susceptibility to DNA rearrangements.
To identify deletion regions critical for human cancer development and progression, we have combined TALEN or CRISPR/Cas9 technologies and in vitro models of cell transformation derived from primary human cells. We introduce targeted chromosomal regions, which are commonly lost during cancer progression, into non-malignant human cells. The created experimental systems, which mimic cancer-associated genetic abnormalities, provide us multiple opportunities. First, it enables us to identify specific chromosomal regions critical for cancer initiation and progression in a high-throughput format. Second, we investigate the cooperative effect of loss of genes, non-coding RNAs, and regulatory elements located within the deleted regions on cell transformation. The proposed model system will also allow us to assess the effect of disruption of the three-dimensional chromosomal network by deletion of specific chromosomal regions on tumorigenic phenotypes. Finally, isogenic cell lines harboring targeted chromosomal alterations will serve as a platform to identify compounds with specificity for particular genetic abnormalities.