Päivi Ojala

    Päivi M. Ojala
    Ph.D., Professor in Cancer Cell Biology & K. Albin Johansson Research Professor

    Research Programs Unit, Translational Cancer Biology
    Medicum
    Faculty of Medicine
    Biomedicum Helsinki

    P.O. Box 63 (Haartmaninkatu 8)
    FI-00014 University of Helsinki
    Finland

    Tel. +358 2 941 59445
    Fax +358 2 941 25610

    firstname.surname@helsinki.fi

Affiliations

Alma-intranet Flammaintra

Research interests of Ojala lab

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. Kaposi’s sarcoma herpesvirus (KSHV), an oncogenic gamma-2 herpesvirus, is genetically equipped to manipulate and deregulate several cellular signaling pathways. Especially AIDS-associated Kaposi’s sarcoma (KS) is strongly linked to immunosuppression and remains a significant health problem worldwide due to persisting HIV epidemic in Africa, and an increase in cases of recurrence even in the HAART-treated AIDS patients.

Previous accomplishments

Our previous accomplishments include demonstration of restoration of p53 function by small molecule inhibitors as a novel therapeutic modality for KSHV-induced lymphomas (J Clin Invest 2007; Oncogene, 2013), viral oncogene-induced DNA damage as an early anti-cancer barrier in Kaposi sarcoma (KS; PLoS Pathogens 2007), viral oncogene-mediated defects of T cell differentiation and lymphoma initiation in vivo (Pekkonen et al., Cell Cycle, 2014), function of KSHV miRNAs in apoptosis inhibition (Suffert et al., PLoS Pathogens 2011), and identification of cellular Pim kinases and epigenetic factors as novel regulators involved in the switch of viral replication programs (reactivation) and tumorigenesis (Cell 2008, and PLoS Pathogens 2009 & 2010). Moreover, we recently developed a novel 3D organotypic cell model for KSHV-infected primary LECs (K-LEC spheroids). These studies led to a significant discovery demonstrating that KSHV can transcriptionally reprogram LECs to a mesenchymal and invasive cell type via endothelial-to-mesenchymal transition (EndMT). We also uncovered a previously uncharacterized Notch-MT1-MMP signaling axis necessary for the virus-induced EndMT (Cell Host & Microbe 2011). Intriguingly, the VEGF-C dependent lymphangiogenic phenotype that we had earlier demonstrated in the K-LEC spheroids (Cancer Cell 2010) was suppressed by the Notch-MT1-MMP axis.

KSHV induced reprogramming and KS pathogenesis

Ojala labPrevious studies demonstrate that LECs display great plasticity and LEC to blood endothelial cell (BEC) transitions are observed under pathological situations. The LEC fate is considered as a consequence of the key transcription factor Prox1-directed lymphatic equilibrium among the cell fate regulators. In this project we are investigating the mechanism and role of Prox1 suppression and identify Prox1 downstream effectors critical for the KSHV-infected 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 viral cancers.

Regulation of KSHV reactivation from latency

KSHV has two stages of lifecycle, latent and lytic.  In latent cells, the viral DNA genome is complexed with cellular histones and duplicated once every cell division. The lytic phase involves viral genome amplification, and production of new virions. The productive, lytic replication phase of the oncogenic KSHV is important for cancer progression and virus spread.Ojala lab We are also continuing our previous work to deepen the molecular understanding of the regulation of the two KSHV viral replication programs, the latent and lytic replication phases (viral reactivation). In our recent siRNA screen for reactivation we discovered that a cell stress response and p53-p21 are activated and required for the viral lytic gene expression (Balistreri et al, in revision). Our current research is aimed to determine how KSHV manipulates components of the host DNA pre-replicative complex and cell cycle during its lytic phase. Understanding the molecular events regulating this process will allow better development of antiviral strategies.

Contribution of cancer cell- lymphatic endothelium crosstalk to cancer progression

Ojala labDuring the last decade, the interaction of cancer cells with the neighboring tissues (stroma) has emerged as a new, important aspect of cancer biology. Although it is becoming clear that these interactions play important roles in cancer progression, little is known of their molecular details and mechanisms of regulation. We are interested in understanding the molecular circuits contributing to melanoma invasion and metastasis. Malignant melanomas disseminate primarily through the lymphatic system, and therefore the project focuses on the interactions of melanoma cells with the lymphatic endothelial cells (LECs). The major research questions are i) to address if melanoma cells cause changes in the LEC identity and function, or ii) if the LECs alter the tumorigenic or metastatic properties of melanoma. We have developed several 2- and 3-dimensional organotypic co-culture cell models to mimic the melanoma-LEC interactions in vivo, and we are applying high-content quantitative imaging, RNA-Seq, functional assays and mouse tumor models to analyze the genes and signaling pathways most affected in melanomas after encountering LECs and vice versa. Revealing the molecular mechanisms of these interactions is crucial for the intervention of metastasis and for improving the very poor prognosis of metastatic melanoma.

Ojala lab