Research on human tumor viruses has been central to development of modern cancer biology and given profound insights into not only cancers associated with infection but also cancer in general. We are using Kaposi’s sarcoma herpesvirus (KSHV), an oncogenic gamma-2 herpesvirus, as a model system to study the virus-host interactions. Kaposi’s sarcoma herpesvirus (KSHV), an oncogenic gamma-2 herpesvirus, is genetically equipped to manipulate and deregulate several cellular signalling pathways. Especially AIDS-associated Kaposi’s sarcoma (KS) is strongly linked to immunosuppression and remains a significant health problem due to persisting HIV epidemic in Africa, and an increase in cases of recurrence even in the HAART-treated AIDS patients. We focus mainly on virus induced alterations of the cell cycle machinery as well as KSHV-induced reprogramming of lymphatic endothelial cells (LECs). Our long-term goal is to identify novel signaling pathways and cellular proteins involved in viral reactivation, which could open new leads that can be pursued for novel intervention and therapeutic strategies against KSHV-associated diseases.
Given our expertise on LEC biology, we have expanded our research focus to study the role of lymphatic endothelium in the tumor microenvironment and cancer metastasis. Since many solid cancers, such as melanoma, spread mainly through lymphatics, we are focusing on the LEC-melanoma crosstalk. We are interested in the changes in the tumorigenic properties of the melanoma cells upon contact with the lymphatic endothelium.
We continued our study on PROX1 down regulation in KSHV-infected LECs and investigated the consequences of this down regulation in KSHV-induced tumorigenesis. In this project we are investigating the mechanism and role of Prox1 suppression and identify Prox1 downstream effectors critical for the KSHV-induced LEC reprogramming and KSHV pathogenesis. The ultimate goal is to identify novel target molecules in the host cells for translation into specific and more effective treatment modalities for cancers.
Another well-established research line in the laboratory involves the interplay between the virus and the host cell cycle. Accumulating evidences support the notion that for an efficient latent-to-lytic switch the virus manipulates the cell cycle and the host replication machinery. Our main focus consists now on identifying the events triggered by the virus to induce such a deep modification of the host. We are also aiming in finding new ways to obtain an efficient and synchronized KSHV reactivation in a wide variety of infected cell types by adopting cutting-edge techniques like dCAS9-induced activation of viral proteins. These approaches will allow us to better control KSHV lytic switch and identify new players in herpesvirus reactivation.
It is becoming evident that the malignant behaviour of tumors is also affected by the crosstalk with the surrounding cellular microenvironment. In order to identify the molecular players elicited by the tumor stroma and increasing the invasiveness of the tumor cells, we have developed several co-culture cell models to mimic the melanoma-LEC interactions in vivo. Our results led to the identification intriguing changes in both the cancer cells and LECs. We are currently addressing the contribution of these changes to melanoma progression and metastasis.
Our previous contributions include demonstration of p53 activation as a novel therapeutic modality for KSHV associated lymphomas and reports on viral oncogene-induced DNA damage and defects in T cell differentiation and lymphoma initiation in vivo.
The switch between the viral latency and lytic replication (virus reactivation) is a critical step in KSHV pathogenesis. . Our previous and recent work has identified cellular Pim kinases, nucleophosmin (NPM) and the p53-p21 axis as novel regulators important for viral reactivation.
We have developed a 3D organotypic cell model for KSHV-infected primary lymphatic endothelial cells (LECs). These studies led to a significant discovery demonstrating that KSHV can transcriptionally reprogram LECs to a less differentiated, mesenchymal-like and invasive cell type. A pivotal role in KSHV-induced reprogramming is played by PROX1, the master regulator of lymphatic cell fate.