Imperial College London

ProfessorPaiviOjala

Faculty of MedicineDepartment of Infectious Disease

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 7594 3971p.ojala Website

 
 
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Location

 

443Medical SchoolSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

67 results found

Monzo HJ, Kalander K, Hyytiäinen MM, Elbasani E, Wall J, Moyano-Galceran L, Tanjore Ramanathan J, Jukonen JJJ, Laakkonen P, Ristimäki A, Carlson JW, Lehti K, Salehi S, Puolakkainen P, Haglund C, Seppänen H, Leppä S, Ojala PMet al., 2023, Efficacy and safety of glycosphingolipid SSEA-4 targeting CAR-T cells in an ovarian carcinoma model., Mol Cancer Ther

Chimeric antigen receptor (CAR) T-cell immunotherapies for solid tumors face critical challenges such as heterogeneous antigen expression. We characterized SSEA-4 cell-surface glycolipid as a target for CAR-T cell therapy. SSEA-4 is mainly expressed during embryogenesis but is also found in several cancer types making it an attractive tumor-associated antigen. Anti-SSEA-4 CAR-T cells were generated and assessed pre-clinically in vitro and in vivo for anti-tumor response and safety. SSEA-4 CAR-T cells effectively eliminated SSEA-4 positive cells in all the tested cancer cell lines whereas SSEA-4 negative cells lines were not targeted. In vivo efficacy and safety studies using NSG mice and the high-grade serous ovarian cancer cell line OVCAR4 demonstrated a remarkable and specific anti-tumor response at all the CAR-T cell doses used. At high T cell doses, CAR-T cell-treated mice showed signs of health deterioration after a follow-up period. However, the severity of toxicity was reduced with a delayed onset when lower CAR-T cell doses were used. Our data demonstrate the efficacy of anti-SSEA-4 CAR-T therapy; however, safety strategies, such as dose-limiting and/or equipping CAR-T cells with combinatorial antigen recognition should be implemented for its potential clinical translation.

Journal article

De Marco RC, Monzo HJ, Ojala PM, 2023, CAR T Cell Therapy: A Versatile Living Drug., Int J Mol Sci, Vol: 24

After seeing a dramatic increase in the development and use of immunotherapy and precision medicine over the past few decades, oncological care now embraces the start of the adoptive cell therapy (ACT) era. This impulse towards a new treatment paradigm has been led by chimeric antigen receptor (CAR) T cells, the only type of ACT medicinal product to be commercialized so far. Brought about by an ever-growing understanding of cellular engineering, CAR T cells are T lymphocytes genetically modified with an appropriate DNA construct, which endows them with expression of a CAR, a fusion protein between a ligand-specific recognition domain, often an antibody-like structure, and the activating signaling domain of the T cell receptor. Through this genetic enhancement, CAR T cells are engineered from a cancer patient's own lymphocytes to better target and kill their cancer cells, and the current amassed data on clinical outcomes point to a stream of bright developments in the near future. Herein, from concept design and present-day manufacturing techniques to pressing hurdles and bright discoveries around the corner, we review and thoroughly describe the state of the art in CAR T cell therapy.

Journal article

Tuohinto K, DiMaio TP, Kiss E, Laakkonen PP, Saharinen P, Karnezis TP, Lagunoff M, Ojala PMPet al., 2023, KSHV infection of endothelial precursor cells with lymphatic characteristics as a novel model for translational Kaposi's sarcoma studies, PLOS PATHOGENS, Vol: 19, ISSN: 1553-7366

Journal article

Tuohinto K, DiMaio TA, Kiss EA, Laakkonen P, Saharinen P, Karnezis T, Lagunoff M, Ojala PMet al., 2022, KSHV infection of endothelial precursor cells with lymphatic characteristics as a novel model for translational Kaposi’s sarcoma studies

<jats:title>Abstract</jats:title><jats:p>Kaposi’s sarcoma herpesvirus (KSHV) is the etiologic agent of Kaposi’s sarcoma (KS), a hyperplasia consisting of enlarged malformed vasculature and spindle-shaped cells, the main proliferative component of KS. While spindle cells express markers of lymphatic and blood endothelium, the origin of spindle cells is unknown. Endothelial precursor cells have been proposed as the source of spindle cells. We previously identified two types of circulating endothelial colony forming cells (ECFCs), ones that expressed markers of blood endothelium and ones that expressed markers of lymphatic endothelium. Here we examined both blood and lymphatic ECFCs infected with KSHV. Lymphatic ECFCs are significantly more susceptible to KSHV infection than the blood ECFCs and maintain the viral episomes during passage in culture while the blood ECFCs lose the viral episome. Only the KSHV-infected lymphatic ECFCs grew to small multicellular colonies in soft agar whereas the infected blood ECFCs and all uninfected ECFCs failed to proliferate. The lymphatic ECFCs express high levels of SOX18, which supported the maintenance of high copy number of KSHV genomes. When implanted subcutaneously into NSG mice, the KSHV-infected lymphatic ECFCs persisted in vivo and recapitulated the phenotype of KS tumor cells with high number of viral genome copies and spindling morphology. These spindle cell hallmarks were significantly reduced when mice were treated with SOX18 inhibitor, SM4. These data suggest that KSHV-infected lymphatic ECFCs can be utilized as a KSHV infection model for in vivo translational studies to test novel inhibitors representing potential treatment modalities for KS.</jats:p><jats:sec><jats:title>Author summary</jats:title><jats:p>Kaposi’s sarcoma herpesvirus (KSHV) is the etiologic agent of Kaposi’s sarcoma (KS). The main proliferative component of KS, spindle cells, expre

Journal article

Vilimova M, Contrant M, Randrianjafy R, Dumas P, Elbasani E, Ojala PM, Pfeffer S, Fender Aet al., 2021, Cis regulation within a cluster of viral microRNAs, NUCLEIC ACIDS RESEARCH, Vol: 49, Pages: 10018-10033, ISSN: 0305-1048

Journal article

Jukonen J, Moyano-Galceran L, Hopfner K, Pietila EA, Lehtinen L, Huhtinen K, Gucciardo E, Hynninen J, Hietanen S, Grenman S, Ojala PM, Carpen O, Lehti Ket al., 2021, Aggressive and recurrent ovarian cancers upregulate ephrinA5, a non-canonical effector of EphA2 signaling duality, SCIENTIFIC REPORTS, Vol: 11, ISSN: 2045-2322

Journal article

Lippert T, Marzec P, Idilli A, Sarek G, Bower M, Farrell P, Ojala PM, Feldhahn N, Boulton SJet al., 2021, Oncogenic herpesvirus KSHV triggers hallmarks of alternative lengthening of telomeres, Nature Communications, Vol: 12, ISSN: 2041-1723

To achieve replicative immortality, cancer cells must activate telomere maintenance mechanisms to prevent telomere shortening. ~85% of cancers circumvent telomeric attrition by re-expressing telomerase, while the remaining ~15% of cancers induce alternative lengthening of telomeres (ALT), which relies on break-induced replication (BIR) and telomere recombination. Although ALT tumours were first reported over 20 years ago, the mechanism of ALT induction remains unclear and no study to date has described a cell-based model that permits the induction of ALT. Here, we demonstrate that infection with Kaposi’s sarcoma herpesvirus (KSHV) induces sustained acquisition of ALT-like features in previously non-ALT cell lines. KSHV-infected cells acquire hallmarks of ALT activity that are also observed in KSHV-associated tumour biopsies. Down-regulating BIR impairs KSHV latency, suggesting that KSHV co-opts ALT for viral functionality. This study uncovers KSHV infection as a means to study telomere maintenance by ALT and reveals features of ALT in KSHV-associated tumours.

Journal article

Alve S, Gramolelli S, Ojala PM, 2021, An Approach to Study Melanoma Invasion and Crosstalk with Lymphatic Endothelial Cell Spheroids in 3D Using Immunofluorescence, MELANOMA, Vol: 2265, Pages: 141-154, ISSN: 1064-3745

Journal article

Elbasani E, Falasco F, Gramolelli S, Nurminen V, Günther T, Weltner J, Balboa D, Grundhoff A, Otonkoski T, Ojala PMet al., 2020, Kaposi's Sarcoma-Associated Herpesvirus Reactivation by Targeting of a dCas9-Based Transcription Activator to the ORF50 Promoter, Viruses, Vol: 12, ISSN: 1999-4915

CRISPR activation (CRISPRa) has revealed great potential as a tool to modulate the expression of targeted cellular genes. Here, we successfully applied the CRISPRa system to trigger the Kaposi's sarcoma-associated herpesvirus (KSHV) reactivation in latently infected cells by selectively activating ORF50 gene directly from the virus genome. We found that a nuclease-deficient Cas9 (dCas9) fused to a destabilization domain (DD) and 12 copies of the VP16 activation domain (VP192) triggered a more efficient KSHV lytic cycle and virus production when guided to two different sites on the ORF50 promoter, instead of only a single site. To our surprise, the virus reactivation induced by binding of the stable DD-dCas9-VP192 on the ORF50 promoter was even more efficient than reactivation induced by ectopic expression of ORF50. This suggests that recruitment of additional transcriptional activators to the ORF50 promoter, in addition to ORF50 itself, are needed for the efficient virus production. Further, we show that CRISPRa can be applied to selectively express the early lytic gene, ORF57, without disturbing the viral latency. Therefore, CRISPRa-based systems can be utilized to facilitate virus-host interaction studies by controlling the expression of not only cellular but also of specific KSHV genes.

Journal article

Gramolelli S, Elbasani E, Tuohinto K, Nurminen V, Guenther T, Kallinen RE, Kaijalainen SP, Diaz R, Grundhoff A, Haglund C, Ziegelbauer JM, Pellinen T, Bower M, Francois M, Ojala PMet al., 2020, Oncogenic herpesvirus engages endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production, Cancer Research, Vol: 80, Pages: 3116-3129, ISSN: 0008-5472

Kaposi sarcoma is a tumor caused by Kaposi sarcoma herpesvirus (KSHV) infection and is thought to originate from lymphatic endothelial cells (LEC). While KSHV establishes latency in virtually all susceptible cell types, LECs support spontaneous expression of oncogenic lytic genes, high viral genome copies, and release of infectious virus. It remains unknown the contribution of spontaneous virus production to the expansion of KSHV-infected tumor cells and the cellular factors that render the lymphatic environment unique to KSHV life cycle. We show here that expansion of the infected cell population, observed in LECs, but not in blood endothelial cells, is dependent on the spontaneous virus production from infected LECs. The drivers of lymphatic endothelium development, SOX18 and PROX1, regulated different steps of the KSHV life cycle. SOX18 enhanced the number of intracellular viral genome copies and bound to the viral origins of replication. Genetic depletion or chemical inhibition of SOX18 caused a decrease of KSHV genome copy numbers. PROX1 interacted with ORF50, the viral initiator of lytic replication, and bound to the KSHV genome in the promoter region of ORF50, increasing its transactivation activity and KSHV spontaneous lytic gene expression and infectious virus release. In Kaposi sarcoma tumors, SOX18 and PROX1 expression correlated with latent and lytic KSHV protein expression. These results demonstrate the importance of two key transcriptional drivers of LEC fate in the regulation of the tumorigenic KSHV life cycle. Moreover, they introduce molecular targeting of SOX18 as a potential novel therapeutic avenue in Kaposi sarcoma.

Journal article

Pyöriä L, Jokinen M, Toppinen M, Salminen H, Vuorinen T, Hukkanen V, Schmotz C, Elbasani E, Ojala PM, Hedman K, Välimaa H, Perdomo MFet al., 2020, HERQ-9 Is a new multiplex PCR for differentiation and quantification of all nine human herpesviruses, mSphere, Vol: 5, ISSN: 2379-5042

Infections with the nine human herpesviruses (HHVs) are globally prevalent and characterized by lifelong persistence. Reactivations can potentially manifest as life-threatening conditions for which the demonstration of viral DNA is essential. In the present study, we developed HERQ-9, a pan-HHV quantitative PCR designed in triplex reactions to differentiate and quantify each of the HHV-DNAs: (i) herpes simplex viruses 1 and 2 and varicella-zoster virus; (ii) Epstein-Barr virus, human cytomegalovirus, and Kaposi's sarcoma-associated herpesvirus; and (iii) HHV-6A, -6B, and -7. The method was validated with prequantified reference standards as well as with mucocutaneous swabs and cerebrospinal fluid, plasma, and tonsillar tissue samples. Our findings highlight the value of multiplexing in the diagnosis of many unsuspected, yet clinically relevant, herpesviruses. In addition, we report here frequent HHV-DNA co-occurrences in clinical samples, including some previously unknown. HERQ-9 exhibited high specificity and sensitivity (LOD95s of ∼10 to ∼17 copies/reaction), with a dynamic range of 101 to 106 copies/μl. Moreover, it performed accurately in the coamplification of both high- and low-abundance targets in the same reaction. In conclusion, we demonstrated that HERQ-9 is suitable for the diagnosis of a plethora of herpesvirus-related diseases. Besides its significance to clinical management, the method is valuable for the assessment of hitherto-unexplored synergistic effects of herpesvirus coinfections. Furthermore, its high sensitivity enables studies on the human virome, often dealing with minute quantities of persisting HHVs.IMPORTANCE By adulthood, almost all humans become infected by at least one herpesvirus (HHV). The maladies inflicted by these microbes extend beyond the initial infection, as they remain inside our cells for life and can reactivate, causing severe diseases. The diagnosis of active infection by these ubiquitous pathogens includes the d

Journal article

Elbasani E, Gramolelli S, Günther T, Gabaev I, Grundhoff A, Ojala PMet al., 2020, Kaposi sarcoma herpesvirus lytic replication is independent of the anaphase promoting complex activity., Journal of Virology, Vol: 94, Pages: 1-17, ISSN: 0022-538X

The anaphase promoting complex or cyclosome (APC/C) is a large E3 ubiquitin ligase, composed of 14 subunits. The activity of APC/C oscillates during the cell cycle to ensure a timely transition through each phase by promoting the degradation of important cell cycle regulators. Of the human herpesviruses, cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) both impair the activity of APC/C during their lytic replication through virus-encoded protein kinases. Here, we addressed if the oncogenic Kaposi sarcoma herpesvirus (KSHV) deregulates the activity of APC/C during the lytic replication cycle. To this end, we have used the well-characterized iSLK.219 cell model of KSHV-infection and established a new infection model of primary lymphatic endothelial cells (LEC) infected with a lytically replicating KSHV BAC16 mutant. In contrast to EBV and HCMV, KSHV lytic cycle occurs while the APC/C is active. Moreover, interfering with the APC/C activity did not lead to major changes in the production of infectious virus. We further investigated whether re-replication stress induced by the unscheduled activation of the APC/C-CDH1 affects the number and integrity of the KSHV viral episomes. Deep sequencing of the viral episomes and host chromosomes in the iSLK.219 cells revealed that while distinct regions in the cellular chromosomes were severely affected by the re-replication stress, the integrity of the viral episomes remained unaltered.IMPORTANCEDNA viruses have evolved complex strategies to gain control over the cell cycle. Several of them target APC/C, a key cellular machinery that controls the timely progression of the cell cycle, by either blocking or enhancing its activity. Here, we investigated the activity of APC/C during the lytic replication cycle of KSHV and found that in contrast to its close relatives, EBV and HCMV, the KSHV lytic replication occurs while the APC/C is active. Perturbing the APC/C activity by depleting a core protein or the adaptor proteins of the c

Journal article

Gungor B, Vanharanta L, Hölttä-Vuori M, Pirhonen J, Petersen NHT, Gramolelli S, Ojala PM, Kirkegaard T, Ikonen Eet al., 2019, HSP70 induces liver X receptor pathway activation and cholesterol reduction in vitro and in vivo, Molecular Metabolism, Vol: 28, Pages: 135-143, ISSN: 2212-8778

OBJECTIVE: Heat Shock Proteins (HSPs) maintain cellular homeostasis under stress. HSP70 represents a major stress-inducible family member and has been identified as a druggable target in inherited cholesterol-sphingolipid storage diseases. We investigated if HSP70 modulates cholesterol accumulation in more common conditions related to atherogenesis. METHODS: We studied the effects of recombinant HSP70 in cholesterol-laden primary macrophages from human blood donors and pharmacological HSP70 upregulation in high-cholesterol diet fed zebrafish. RESULTS: Recombinant HSP70 facilitated cholesterol removal from primary human macrophage foam cells. RNA sequencing revealed that HSP70 induced a robust transcriptional re-programming, including upregulation of key targets of liver X receptors (LXR), master regulators of whole-body cholesterol removal. Mechanistically, HSP70 interacted with the macrophage LXRalpha promoter, increased LXRalpha and its target mRNAs, and led to elevated levels of key proteins facilitating cholesterol efflux, including ATP-binding cassette transporters A1 and G1. Pharmacological augmentation of endogenous HSP70 in high-cholesterol diet fed zebrafish activated LXR and its target mRNAs and reduced cholesterol storage at the whole organism level. CONCLUSION: These data demonstrate that HSP70 exerts a cholesterol lowering effect in primary human cells and animals and uncover a nuclear action of HSP70 in mediating cross-talk between HSP and LXR transcriptional regulation.

Journal article

Kasurinen A, Gramolelli S, Hagstrom J, Laitinen A, Kokkola A, Miki Y, Lehti K, Yashiro M, Ojala PM, Bockelman C, Haglund Cet al., 2019, High tissue MMP14 expression predicts worse survival in gastric cancer, particularly with a low PROX1, Cancer Medicine, Vol: 8, Pages: 6995-7005, ISSN: 2045-7634

Matrix metalloproteinase 14 (MMP14), a membrane‐associated matrix metalloproteinase, has been shown to influence the invasion and metastasis of several solid tumors. Prospero homeobox protein 1 (PROX1), involved in the development and cell fate determination, is also expressed in malignant diseases functioning either as a tumor‐suppressing or oncogenic factor. In certain cancers PROX1 appears to transcriptionally suppress MMP14 expression. This study, therefore, aimed to explore the association between MMP14 and PROX1 and understand their potential as prognostic biomarkers in gastric cancer. The cohort consisted of 313 individuals operated for gastric adenocarcinoma between 2000 and 2009 in the Department of Surgery, Helsinki University Hospital. MMP14 and PROX1 expressions were studied using immunohistochemistry in the patient sample and using immunoblotting and immunofluorescence in gastric cancer cell lines. We generated survival curves using the Kaplan‐Meier method, determining significance via the log‐rank test. A high MMP14 expression associated with being ≥67 years (P = .041), while a positive nuclear PROX1 expression associated with tumors of a diffuse histological type (P = .041) and a high cytoplasmic PROX1 expression (P < .001). Five‐year disease‐specific survival among patients with a high MMP14 expression was 35.9% (95% confidence interval [CI] 24.9‐46.9), compared to 45.3% (95% CI 38.0‐52.6) for patients with a low MMP14 (P = .030). Survival was worse specifically among those with a high MMP14 and absent nuclear PROX1 expression (hazard ratio [HR] 1.65; 95% CI 1.09‐2.51; P = .019). Thus, this study confirms that a high MMP14 expression predicts a worse survival in gastric cancer, revealing for the first time that survival is particularly worse when PROX1 is low.

Journal article

Gonzalez-Molina J, Gramolelli S, Liao Z, Carlson JW, Ojala PM, Lehti Ket al., 2019, MMP14 in sarcoma: A regulator of tumor microenvironment communication in connective tissues, Cells, Vol: 8, Pages: 1-24, ISSN: 2073-4409

Sarcomas are deadly malignant tumors of mesenchymal origin occurring at all ages. The expression and function of the membrane-type matrix metalloproteinase MMP14 is closely related to the mesenchymal cell phenotype, and it is highly expressed in most sarcomas. MMP14 regulates the activity of multiple extracellular and plasma membrane proteins, influencing cell–cell and cell–extracellular matrix (ECM) communication. This regulation mediates processes such as ECM degradation and remodeling, cell invasion, and cancer metastasis. Thus, a comprehensive understanding of the biology of MMP14 in sarcomas will shed light on the mechanisms controlling the key processes in these diseases. Here, we provide an overview of the function and regulation of MMP14 and we discuss their relationship with clinical and pre-clinical MMP14 data in both adult and childhood sarcomas.

Journal article

Paatero I, Alve S, Gramolelli S, Ivaska J, Ojala PMet al., 2018, Zebrafish embryo xenograft and metastasis assay, Bio-protocol, Vol: 8, ISSN: 2331-8325

Xenograft models, and in particular the mouse xenograft model, where human cancer cells are transplanted into immunocompromised mice, have been used extensively in cancer studies. Although these models have contributed enormously to our understanding of cancer biology, the zebrafish xenograft model offers several advantages over the mouse model. Zebrafish embryos can be easily cultured in large quantities, are small and easy to handle, making it possible to use a high number of embryos for each experimental condition. Young embryos lack an efficient immune system. Therefore the injected cancer cells are not rejected, and the formation of primary tumors and micrometastases is rapid. Transparency of the embryos enables imaging of primary tumors and metastases in an intact and living embryo. Here we describe a method where GFP expressing tumor cells are injected into pericardial space of zebrafish embryos. At four days post-injection, the embryos are imaged and the formation of primary tumor and distant micrometastases are analyzed.

Journal article

Gramolelli S, Cheng J, Martinez-Corral I, Vähä-Koskela M, Elbasani E, Kaivanto E, Rantanen V, Tuohinto K, Hautaniemi S, Bower M, Haglund C, Alitalo K, Mäkinen T, Petrova T, Lehti K, Ojala PMet al., 2018, PROX1 is a transcriptional regulator of MMP14, Scientific Reports, Vol: 8, ISSN: 2045-2322

The transcription factor PROX1 is essential for development and cell fate specification. Its function in cancer is context-dependent since PROX1 has been shown to play both oncogenic and tumour suppressive roles. Here, we show that PROX1 suppresses the transcription of MMP14, a metalloprotease involved in angiogenesis and cancer invasion, by binding and suppressing the activity of MMP14 promoter. Prox1 deletion in murine dermal lymphatic vessels in vivo and in human LECs increased MMP14 expression. In a hepatocellular carcinoma cell line expressing high endogenous levels of PROX1, its silencing increased both MMP14 expression and MMP14-dependent invasion in 3D. Moreover, PROX1 ectopic expression reduced the MMP14-dependent 3D invasiveness of breast cancer cells and angiogenic sprouting of blood endothelial cells in conjunction with MMP14 suppression. Our study uncovers a new transcriptional regulatory mechanism of cancer cell invasion and endothelial cell specification.

Journal article

Ojala PM, 2018, Lymphatic endothelium stimulates melanoma metastasis and invasion via MMP14-dependent Notch3 and 1-integrin activation, eLife, Vol: 7, ISSN: 2050-084X

Lymphatic invasion and lymph node metastasis correlate with poor clinical outcome in melanoma. However, the mechanisms of lymphatic dissemination in distant metastasis remain incompletely understood. We show here that exposure of expansively growing human WM852 melanoma cells, but not singly invasive Bowes cells, to lymphatic endothelial cells (LEC) in 3D co-culture facilitates melanoma distant organ metastasis in mice. To dissect the underlying molecular mechanisms, we established LEC co-cultures with different melanoma cells originating from primary tumors or metastases. Notably, the expansively growing metastatic melanoma cells adopted an invasively sprouting phenotype in 3D matrix that was dependent on MMP14, Notch3 and β1-integrin. Unexpectedly, MMP14 was necessary for LEC-induced Notch3 induction and coincident β1-integrin activation. Moreover, MMP14 and Notch3 were required for LEC-mediated metastasis of zebrafish xenografts. This study uncovers a unique mechanism whereby LEC contact promotes melanoma metastasis by inducing a reversible switch from 3D growth to invasively sprouting cell phenotype.

Journal article

Gramolelli S, Ojala PM, 2017, Kaposi's sarcoma herpesvirus-induced endothelial cell reprogramming supports viral persistence and contributes to Kaposi's sarcoma tumorigenesis, CURRENT OPINION IN VIROLOGY, Vol: 26, Pages: 156-162, ISSN: 1879-6257

Kaposi's sarcoma (KS) is an endothelial tumor causally linked to Kaposi's sarcoma herpesvirus (KSHV) infection. At early stages of KS, inflammation and aberrant neoangiogenesis are predominant, while at late stages the disease is characterized by the proliferation of KSHV-infected spindle cells (SC). Since KSHV infection modifies the endothelial cell (EC) identity, the origin of SCs remains elusive. Yet, pieces of evidence indicate the lymphatic origin. KSHV-infected ECs display increased proliferative, angiogenic and migratory capacities which account for KS oncogenesis. Here we propose a model in which KSHV reprograms the EC identity, induces DNA damage and establishes a dysregulated gene expression program involving interplay of latent and lytic genes allowing continuous reinfection of ECs attracted to the tumor by the secretion of virus-induced cellular factors.

Journal article

Wang J, Okkeri J, Pavic K, Wang Z, Kauko O, Halonen T, Sarek G, Ojala PM, Rao Z, Xu W, Westermarck Jet al., 2017, Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56, EMBO REPORTS, Vol: 18, Pages: 437-450, ISSN: 1469-221X

Protein phosphatase 2A (PP2A) is a critical human tumor suppressor. Cancerous inhibitor of PP2A (CIP2A) supports the activity of several critical cancer drivers (Akt, MYC, E2F1) and promotes malignancy in most cancer types via PP2A inhibition. However, the 3D structure of CIP2A has not been solved, and it remains enigmatic how it interacts with PP2A. Here, we show by yeast two‐hybrid assays, and subsequent validation experiments, that CIP2A forms homodimers. The homodimerization of CIP2A is confirmed by solving the crystal structure of an N‐terminal CIP2A fragment (amino acids 1–560) at 3.0 Å resolution, and by subsequent structure‐based mutational analyses of the dimerization interface. We further describe that the CIP2A dimer interacts with the PP2A subunits B56α and B56γ. CIP2A binds to the B56 proteins via a conserved N‐terminal region, and dimerization promotes B56 binding. Intriguingly, inhibition of either CIP2A dimerization or B56α/γ expression destabilizes CIP2A, indicating opportunities for controlled degradation. These results provide the first structure–function analysis of the interaction of CIP2A with PP2A/B56 and have direct implications for its targeting in cancer therapy.

Journal article

Balistreri G, Viiliäinen J, Turunen M, Diaz R, Lyly L, Pekkonen P, Rantala J, Ojala K, Sarek G, Teesalu M, Denisova O, Peltonen K, Julkunen I, Varjosalo M, Kainov D, Kallioniemi O, Laiho M, Taipale J, Hautaniemi S, Ojala PMet al., 2016, Oncogenic herpesvirus utilizes stress-induced cell cycle checkpoints for efficient lytic replication, Plos Pathogens, Vol: 12, ISSN: 1553-7374

Kaposi's sarcoma herpesvirus (KSHV) causes Kaposi's sarcoma and certain lymphoproliferative malignancies. Latent infection is established in the majority of tumor cells, whereas lytic replication is reactivated in a small fraction of cells, which is important for both virus spread and disease progression. A siRNA screen for novel regulators of KSHV reactivation identified the E3 ubiquitin ligase MDM2 as a negative regulator of viral reactivation. Depletion of MDM2, a repressor of p53, favored efficient activation of the viral lytic transcription program and viral reactivation. During lytic replication cells activated a p53 response, accumulated DNA damage and arrested at G2-phase. Depletion of p21, a p53 target gene, restored cell cycle progression and thereby impaired the virus reactivation cascade delaying the onset of virus replication induced cytopathic effect. Herpesviruses are known to reactivate in response to different kinds of stress, and our study now highlights the molecular events in the stressed host cell that KSHV has evolved to utilize to ensure efficient viral lytic replication.

Journal article

Aavikko M, Kaasinen E, Nieminen JK, Byun M, Donner I, Mancuso R, Ferrante P, Clerici M, Brambilla L, Tourlaki A, Sarid R, Guttman-Yassky E, Taipale M, Morgunova E, Pekkonen P, Ojala PM, Pukkala E, Casanova J-L, Vaarala O, Vahteristo P, Aaltonen LAet al., 2015, Whole-Genome Sequencing Identifies STAT4 as a Putative Susceptibility Gene in Classic Kaposi Sarcoma, JOURNAL OF INFECTIOUS DISEASES, Vol: 211, Pages: 1842-1851, ISSN: 0022-1899

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Tatti O, Gucciardo E, Pekkonen P, Holopainen T, Louhimo R, Repo P, Maliniemi P, Lohi J, Rantanen V, Hautaniemi S, Alitalo K, Ranki A, Ojala PM, Keski-Oja J, Lehti Ket al., 2015, MMP16 Mediates a Proteolytic Switch to Promote Cell-Cell Adhesion, Collagen Alignment, and Lymphatic Invasion in Melanoma, CANCER RESEARCH, Vol: 75, Pages: 2083-2094, ISSN: 0008-5472

Journal article

Pekkonen P, Jarviluoma A, Zinovkina N, Cvrljevic A, Prakash S, Westermarck J, Evan GI, Cesarman E, Verschuren EW, Ojala PMet al., 2014, KSHV viral cyclin interferes with T-cell development and induces lymphoma through Cdk6 and Notch activation in vivo, CELL CYCLE, Vol: 13, Pages: 3670-3684, ISSN: 1538-4101

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Ojala PM, Schulz TF, 2014, Manipulation of endothelial cells by KSHV: Implications for angiogenesis and aberrant vascular differentiation, SEMINARS IN CANCER BIOLOGY, Vol: 26, Pages: 69-77, ISSN: 1044-579X

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Ojala PM, 2013, Naughty chaperone as a target for viral cancer, BLOOD, Vol: 122, Pages: 2767-2768, ISSN: 0006-4971

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Santag S, Jaeger W, Karsten CB, Kati S, Pietrek M, Steinemann D, Sarek G, Ojala PM, Schulz TFet al., 2013, Recruitment of the tumour suppressor protein p73 by Kaposi's Sarcoma Herpesvirus latent nuclear antigen contributes to the survival of primary effusion lymphoma cells, ONCOGENE, Vol: 32, Pages: 3676-3685, ISSN: 0950-9232

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Kakkola L, Denisova OV, Tynell J, Viiliainen J, Ysenbaert T, Matos RC, Nagaraj A, Ohman T, Kuivanen S, Paavilainen H, Feng L, Yadav B, Julkunen I, Vapalahti O, Hukkanen V, Stenman J, Aittokallio T, Verschuren EW, Ojala PM, Nyman T, Saelens X, Dzeyk K, Kainov DEet al., 2013, Anticancer compound ABT-263 accelerates apoptosis in virus-infected cells and imbalances cytokine production and lowers survival rates of infected mice, CELL DEATH & DISEASE, Vol: 4, ISSN: 2041-4889

Journal article

Sarek G, Ma L, Enback J, Jarviluoma A, Moreau P, Haas J, Gessain A, Koskinen PJ, Laakkonen P, Ojala PMet al., 2013, Kaposi's sarcoma herpesvirus lytic replication compromises apoptotic response to p53 reactivation in virus-induced lymphomas, ONCOGENE, Vol: 32, Pages: 1091-1098, ISSN: 0950-9232

Journal article

Pekkonen P, Ojala PM, 2013, [Viral infection--a diverse causative agent of cancer]., Duodecim, Vol: 129, Pages: 1545-1551, ISSN: 0012-7183

Viral infections are a common cause for the development of cancer. Most common among the cancer-inducing viruses are human papillomaviruses, which cause cervical cancer among other things. Cancer viruses aim to keep their host cells alive and simultaneously use their oncogenes to interfere with cellular phenomena such as proliferation and programmed cell death. The most effective way of preventing viral cancers is to reduce the frequency of cancer virus infections by using vaccinations and by intervening in high-risk behavior. In addition, the infections must be detected and treated in advance of cancer development.

Journal article

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