المؤلفون: Tuohinto, Krista, DiMaio, Terri P., Kiss, Elina, Laakkonen, Pirjo P., Saharinen, Pipsa, Karnezis, Tara P., Lagunoff, Michael, Ojala, Päivi M. P.

المساهمون: Research Programs Unit, CAN-PRO - Translational Cancer Medicine Program, STEMM - Stem Cells and Metabolism Research Program, Helsinki Institute of Life Science HiLIFE, Infra, Pirjo Maarit Laakkonen / Principal Investigator, Department of Biochemistry and Developmental Biology, Helsinki In Vivo Animal Imaging Platform (HAIP), Department of Pathology, Medicum

مصطلحات موضوعية: Progenitor cells, Herpesvirus-infection, Gene-expression, Spindle cells, Origin, Activation, Suggests, Program, Latency, Leads, 3111 Biomedicine, 11832 Microbiology and virology

الوصف: Author summaryKaposi's sarcoma herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS). The main proliferative component of KS, spindle cells, express markers of lymphatic and blood endothelium. Endothelial precursor cells, which are circulating endothelial colony forming cells (ECFCs), have been proposed as the source of spindle cells. Here we examined both blood and lymphatic ECFCs infected with KSHV. Lymphatic ECFCs are readily infected by KSHV, maintain the viral episomes and show modest transformation of the cells, which the infected blood ECFCs and all uninfected ECFCs failed to show. The lymphatic ECFCs express SOX18, which supported the maintenance of high copy numbers of KSHV genomes. The KSHV-infected lymphatic ECFCs persisted in vivo and recapitulated the phenotype of KS tumor cells such as high number of viral genome copies and spindling morphology. These KS tumor cell hallmarks were significantly reduced by SOX18 chemical inhibition using a small molecule SM4 treatment. These data suggest that KSHV-infected lymphatic ECFCs could be the progenitors of KS spindle cells and are a promising model for the translational studies to develop new therapies for KS.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 ...

وصف الملف: application/pdf

العلاقة: Tuohinto , K , DiMaio , T P , Kiss , E , Laakkonen , P P , Saharinen , P , Karnezis , T P , Lagunoff , M & Ojala , P M P 2023 , ' KSHV infection of endothelial precursor cells with lymphatic characteristics as a novel model for translational Kaposi's sarcoma studies ' , PLoS Pathogens , vol. 19 , no. 1 , e1010753 . https://doi.org/10.1371/journal.ppat.1010753Test; ORCID: /0000-0002-9620-095X/work/130600073; 2c77889a-daae-4d48-9bbc-5db9a1ffe7f5; http://hdl.handle.net/10138/356008Test; 000935334400001

الإتاحة: http://hdl.handle.net/10138/356008Test

المؤلفون: Gramolelli, Silvia, Cheng, Jianpin, Martinez-Corral, Ines, Vaha-Koskela, Markus, Elbasani, Endrit, Kaivanto, Elisa, Rantanen, Ville, Tuohinto, Krista, Hautaniemi, Sampsa, Bower, Mark, Haglund, Caj, Alitalo, Kari, Mäkinen, Taija, Petrova, Tatiana V., Lehti, Kaisa, Ojala, Paivi M.

المصدر: Scientific Reports. 8

الوصف: 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.

وصف الملف: electronic

الوصول الحر: https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-387452Test
https://doi.org/10.1038/s41598-018-27739-wTest
https://uu.diva-portal.org/smash/get/diva2:1330026/FULLTEXT01.pdfTest

المؤلفون: Pekkonen, Pirita, Alve, Sanni, Balistreri, Giuseppe, Gramolelli, Silvia, Tatti-Bugaeva, Olga, Paatero, Ilkka, Niiranen, Otso, Tuohinto, Krista, Perala, Nina, Taiwo, Adewale, Zinovkina, Nadezhda, Repo, Pauliina, Icay, Katherine, Ivaska, Joanna, Saharinen, Pipsa, Hautaniemi, Sampsa, Lehti, Kaisa, Ojala, Paivi M.

المساهمون: Research Programs Unit, Translational Cancer Biology (TCB) Research Programme, Genome-Scale Biology (GSB) Research Program, Pipsa Ilona Saharinen / Principal Investigator, Sampsa Hautaniemi / Principal Investigator, Bioinformatics, Kaisa Irene Lehti / Principal Investigator, Päivi Ojala / Research director

مصطلحات موضوعية: TO-MESENCHYMAL TRANSITION, TUMOR PROGRESSION, NODE METASTASIS, CELL-ADHESION, CANCER, METALLOPROTEINASES, EXPRESSION, PLATFORM, VESSELS, CCR7, 3111 Biomedicine

الوصف: 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 beta 1-integrin. Unexpectedly, MMP14 was necessary for LEC-induced Notch3 induction and coincident beta 1-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. ; Peer reviewed

وصف الملف: application/pdf

العلاقة: Terveyden Tutkimuksen Toimi-kunta 307366 Johanna Ivaska Pipsa Saharinen Paivi M Ojala; Pekkonen , P , Alve , S , Balistreri , G , Gramolelli , S , Tatti-Bugaeva , O , Paatero , I , Niiranen , O , Tuohinto , K , Perala , N , Taiwo , A , Zinovkina , N , Repo , P , Icay , K , Ivaska , J , Saharinen , P , Hautaniemi , S , Lehti , K & Ojala , P M 2018 , ' Lymphatic endothelium stimulates melanoma metastasis and invasion via MMP14-dependent Notch3 and beta 1-integrin activation ' , eLife , vol. 7 , 32490 . https://doi.org/10.7554/eLife.32490Test; ORCID: /0000-0002-7749-2694/work/44998566; ORCID: /0000-0002-9257-9376/work/90907025; 85049593514; cba1f277-1169-4721-b243-c8325363fca1; http://hdl.handle.net/10138/235268Test; 000431114900001

الإتاحة: http://hdl.handle.net/10138/235268Test

المؤلفون: Pekkonen, Pirita, Alve, Sanni, Balistreri, Giuseppe, Gramolelli, Silvia, Tatti-Bugaeva, Olga, Paatero, Ilkka, Niiranen, Otso, Tuohinto, Krista, Perälä, Nina, Taiwo, Adewale, Zinovkina, Nadezhda, Repo, Pauliina, Icay, Katherine, Ivaska, Johanna, Saharinen, Pipsa, Hautaniemi, Sampsa, Lehti, Kaisa, Ojala, Päivi M

المساهمون: Terveyden Tutkimuksen Toimikunta, Finnish Cancer Foundation, Sigrid Juséliuksen Säätiö, University of Helsinki, University of Helsinki Foundation, Suomen Lääketieteen Säätiö, Emil Aaltosen Säätiö

المصدر: eLife ; volume 7 ; ISSN 2050-084X

الوصف: 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.

الإتاحة: https://doi.org/10.7554/elife.32490Test
https://cdn.elifesciences.org/articles/32490/elife-32490-v2.pdfTest
https://cdn.elifesciences.org/articles/32490/elife-32490-v2.xmlTest
https://elifesciences.org/articles/32490Test

المؤلفون: Gramolelli, Silvia, Elbasani, Endrit, Tuohinto, Krista, Nurminen, Veijo, Günther, Thomas, Kallinen, Riikka E., Kaijalainen, Seppo P., Diaz, Raquel, Grundhoff, Adam, Haglund, Caj, Ziegelbauer, Joseph M., Pellinen, Teijo, Bower, Mark, Francois, Mathias, Ojala, Päivi M.

مصطلحات موضوعية: Cancer Research, Oncology

الوصف: 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.Significance: SOX18 and PROX1, central regulators of lymphatic development, are key factors for KSHV genome maintenance and lytic cycle in lymphatic endothelial cells, supporting Kaposi sarcoma tumorigenesis and representing attractive therapeutic targets.

العلاقة: orcid:0000-0002-9846-6882; Not set; 307366; 309544; 324487; 1111169; 1164000

الإتاحة: https://doi.org/10.1158/0008-5472.can-19-3103Test
https://espace.library.uq.edu.au/view/UQ:fbd1173Test

المؤلفون: Tuohinto, Krista, Ojala, Päivi

المساهمون: Tutkimusohjelmayksikkö, Translationaalisen syöpäbiologian tutkimusohjelma, Helsingin yliopisto, Lääketieteellinen tiedekunta, Patologian osasto, Medicum

مصطلحات موضوعية: Neoplasms, +virology, +therapy, Epstein-Barr Virus Infections, Sarcoma, Kaposi, Papillomavirus Infections, Lymphoproliferative Disorders, Immunization Programs, HIV Infections, Hepatitis B, Hepatitis C, 3111 Biolääketieteet, 3122 Syöpätaudit

الوصف: Selvittämällä virusten syöpää aiheuttavia mekanismeja pystytään paremmin kehittämään rokotteita.

وصف الملف: application/pdf

العلاقة: Tuohinto , K & Ojala , P 2019 , ' Virukset ja syöpä - mitä uutta? ' , Suomen lääkärilehti , Vuosikerta. 74 , Nro 9 , Sivut 511-511a . < https://www.laakarilehti.fi/pdf/2019/SLL92019-511.pdfTest >; RIS: urn:9A5B2DA42C1A748AF31217CE002B33A0; 0928a90f-3789-4d4f-9eed-831ed13d7abb; http://hdl.handle.net/10138/314528Test

الإتاحة: http://hdl.handle.net/10138/314528Test

المؤلفون: Tuohinto, Krista, Ojala, Päivi

المساهمون: Tutkimusohjelmayksikkö, Translationaalisen syöpäbiologian tutkimusohjelma, Helsingin yliopisto, Lääketieteellinen tiedekunta, Patologian osasto, Medicum

مصطلحات موضوعية: Epstein-Barr Virus Infections, 3111 Biolääketieteet, 3122 Syöpätaudit, +therapy, Immunization Programs, Neoplasms, +virology, Papillomavirus Infections, HIV Infections, Hepatitis B, Sarcoma, Kaposi, Hepatitis C, Lymphoproliferative Disorders

الوصف: Selvittämällä virusten syöpää aiheuttavia mekanismeja pystytään paremmin kehittämään rokotteita.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=od______1593::a2add6daf2be6ef91324d4532a197680Test
http://hdl.handle.net/10138/314528Test

المؤلفون: Pekkonen, Pirita, Alve, Sanni, Balistreri, Giuseppe, Gramolelli, Silvia, Tatti-Bugaeva, Olga, Paatero, Ilkka, Niiranen, Otso, Tuohinto, Krista, Perälä, Nina, Taiwo, Adewale, Zinovkina, Nadezhda, Repo, Pauliina, Icay, Katherine, Ivaska, Johanna, Saharinen, Pipsa, Hautaniemi, Sampsa, Lehti, Kaisa, Ojala, Päivi M

الإتاحة: https://doi.org/10.7554/elife.32490.032Test

المؤلفون: Tuohinto, Krista

المساهمون: Helsingin yliopisto, Lääketieteellinen tiedekunta, University of Helsinki, Faculty of Medicine, Helsingfors universitet, Medicinska fakulteten

مصطلحات موضوعية: Translational Cancer Biology, Translationaalinen syöpäbiologia

الوصف: Kaposi’s sarcoma herpesvirus (KSHV), also called human herpesvirus 8 (HHV-8), was discovered following the AIDS-epidemic as the causative agent of Kaposi’s sarcoma (KS), an angiogenic endothelial tumor of the skin, and of two rare lymphoproliferative diseases, primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). Infection by KSHV displays two life cycle phases; latent and lytic replication. In latency, the virus stays dormant within the host, expressing only a few genes and no viral particles are produced. Latency is the default mode of infection, however, upon appropriate induction the virus reactivates to express all of its genes and replicate viral DNA during the productive lytic replication, culminating with the release of infectious progeny particles and lysis of the host cells. Virus reactivation from latency to the lytic replication is an essential step in the KS pathogenesis. Upon KSHV infection, endothelial cells (EC) undergo reprogramming towards spindle cell, the principal proliferating cell in advanced KS lesions. The transcription factor prospero related homeobox gene Prox1 has an important role in mediating the effects of KSHV on EC reprogramming, contributing to the KS development. Prox1 is the master regulator of lymphatic endothelial cell fate, and its expression is manipulated during the KSHV infection. However, the role of Prox1 in the KSHV life cycle and lytic reactivation has not been studied. To elucidate the role of Prox1 in KSHV reactivation from latency, the effect of ectopic expression of Prox1 on the lytic gene and protein expression in both latent and reactivated KSHV-infected cells was studied. This led to a significant increase in KSHV lytic gene and protein expression, suggesting Prox1 as a positive regulator of KSHV lytic replication. Moreover, Prox1 wild-type, but not its DNA-binding deficient mutant, could significantly increase the release of infectious virions. To investigate the expression levels of Prox1 during KSHV infection, infection kinetics assay ...

وصف الملف: application/pdf

العلاقة: URN:NBN:fi:hulib-201806152722; http://hdl.handle.net/10138/236389Test

الإتاحة: http://hdl.handle.net/10138/236389Test