Syöpätutkimus

Yksikön ryhmät tutkivat pahanlaatuisten kasvaimien syntymekanismeja, ja kehittävät syövän diagnostiikkaa ja hoitoa.

Yksikön johtaja

Tutkimusryhmät

Klaus Elenius: Actionable Receptor Tyrosine Kinase Signaling

Klaus Elenius, MD PhD, Professor of Medical Biochemistry

Contact: klaus.elenius@utu.fi

Description of Research

Our goal is to understand how receptor tyrosine kinases (RTK) regulate the pathogenesis of human diseases, such as cancer and cardiovascular disorders. This information is needed for the development of molecularly targeted therapies and tools to predict therapeutic responses. The work mainly focuses on the ERBB family of RTKs. The laboratory has contributed to the field by e.g. by characterizing novel RTK signaling mechanisms, by identifying new ERBB4 isoforms, and by identifying clinically actionable ERBB mutations in cancer tissues.

Current topics

Predictive and actionable ERBB mutations in cancer.
A novel cleavage-dependent RTK signaling mechanism.
Non-genetic mechanisms of RTK signaling in cancer drug resistance.
RTK motifs in determining receptor localization and association with signaling complexes.

Research group members

Senior researchers: Anne Jokilammi
PhD students: Deepankar Chakroborty, Juho Heliste, Marika Koivu, Johannes Merilahti, Veera Ojala, Fred Saarinen, Katri Vaparanta
Other students: Kaisa Aalto, Peppi Kirjalainen, Peppi Suominen, Jori Torkkila
Technicians: Maria Tuominen

Recent key publications

Koivu, M. A. K., Chakroborty, D., Tamirat, M. Z., Johnson, M. S., Kurppa, K. J., and Elenius, K. (2020) Identification of predictive ERBB mutations by leveraging publicly available cell line databases. Mol. Cancer. Ther. Accepted.
Ojala, V. K., Knittle, A.M., Kirjalainen, P., Merilahti, J. A. M., Kortesoja, M., Tvorogov, D., Vaparanta, K., Lin, S., Kast, J., Pulliainen, A.T., Kurppa, K. J., and Elenius, K. (2020) The guanine nucleotide exchange factor VAV3 participates in ERBB4-mediated cancer cell migration. J. Biol. Chem. 295:11559-71.
Chakroborty, D., Kurppa, K. J., Paatero, I., Ojala, V. K., Koivu, M., Tamirat, M. Z., Koivunen, J. P., Jänne, P. A., Johnson, M. S., Elo, L.L., and Elenius K. (2019) An unbiased in vitro screen for activating epidermal growth factor mutations. J. Biol. Chem. 294:9377-89.
Paatero, I., Veikkolainen, V., Mäenpää, M., Schmelzer, E., Belting, H.-G., Pelliniemi, L.J., and Elenius, K. (2019). ErbB4 tyrosine kinase inhibition impairs neuromuscular development in zebrafish embryos. Mol. Biol. Cell. 30:209-18.
Merilahti, A. M., and Elenius, K. (2019) Gamma-secretase-dependent signaling of receptor tyrosine kinases. Oncogene. 38:151-63.

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Maria Gardberg: Novel fusion genes in glioblastoma and melanoma

Maria Gardberg, MD PhD, Adjunct Professor in Neuropathology and Clinical Lecturer

Contact: magard@utu.fi

Description of Research

Our group studies molecular mechanisms in cancer. We search for fusion genes in cancer tissue and in cancer cell lines, with emphasis on glioblastoma and melanoma. In cellular studies, we test found fusion genes for oncogenic properties using knockdown and overexpression strategies, measuring their impact on cellular functions. Ultimately, we aim to gain insight to the mechanisms of cancer cell migration and to find therapeutic targets for personalized treatment.

Current topics

Characterization of fusion-gene associated protein expression in normal tissues
Gene expression profiling analysis of EWSR1-CREM fusion oncogene-induced transcription
Fusion genes in primary glioblastoma cell lines

Research group members

Senior researchers: Vanina Dahlstöm-Heuser, Katri Orte
PhD students: Heidi Kaprio
Other students: Lotta Saustila

Recent key publications

Heuser, VD, Kiviniemi, Aida, Lehtinen, L, Munthe, S, Kristensen, BW, Posti, JP, Sipilä, JOT, Vuorinen, V, Carpén, O, Gardberg, M: Multiple formin proteins participate in glioblastoma migration. BMC Cancer 2020.
Priesterbach-Ackley, LP, Boldt, HB, Petersen, JK, Bervoets, N, Scheie, D, Ulhøi, BP, Gardberg, M, Brännström, T, Torp, SH, Aronica, E, Küsters, B, den Dunnen, WFA, de Vos, FY, Wesseling, P, de Leng, WWJ, Kristensen, BW. Brain tumour diagnostics using a DNA methylation-based classifier as a diagnostic support tool. Neuropathology and Applied Neurobiology. 2020.
Sievers P, Appay R, Schrimpf D, Stichel D, Reuss DE, Wefers AK, Gardberg M et al. Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1. Acta Neuropathol. 2019.
Manninen AA, Gardberg M, Juteau S, Ilmonen S, Jukonen J, Andersson N, et al. BRAF immunohistochemistry predicts sentinel lymph node involvement in intermediate thickness melanomas. PLoS One. 2019 April 30;14(4):e0216043.
Kiviniemi A, Gardberg M, Ek P, Frantzen J, Bobacka J, Minn H. Gadolinium retention in gliomas and adjacent normal brain tissue: association with tumor contrast enhancement and linear/macrocyclic agents. Neuroradiology. 2019.

Description of Research

Our laboratory focuses on translational research of ovarian cancer in a multidisciplinary environment. Specifically, we study mechanisms of drug resistance and identify biomarkers for prediction of treatment response and for early diagnostics. In collaboration with local gynaecological oncologists, we aim to bring their discoveries as part of the clinical work to improve the outcome of ovarian cancer. More details: project-hercules.eu

Current topics

Comprehensive characterization and effective combinatorial targeting of high-grade serous ovarian cancer via single-cell analysis (HERCULES-project)
Nanoparticle aided glycovariant blood biomarkers for the early detection of epithelial ovarian cancer
Characterization of novel fusion genes as putative drug targets for high-grade serous ovarian cancer

Research group members

Senior researchers: Vanina Dahlstöm-Heuser, Katja Kaipio, Tarja Lamminen, Laura Lehtinen
PhD students: Naziha Mansuri, Maija Peippo, Minna Peippo, Heidi Rausio, Pia Roering
Other students: Sofia Haapala, Milla Holmén

Recent key publications

Salminen L, Nadeem N, Rolfsen A, Dørum A, Grénman S, Hietanen S, Heinosalo T, Perheentupa A, Poutanen M, Bolstad N, Carpén O, Lamminmäki U, Pettersson K, Gidwani K, Hynninen J, and Huhtinen K. Exploratory analysis of CA125-MGL and -STn glycoforms in the differential diagnostics of pelvic masses. J Appl Lab Med. 2020; 5:263-272.
Heuser, VD, Kiviniemi A, Lehtinen L, Munthe S, Winther Kristensen B, Posti J, Sipilä JOT, Vuorinen V, Carpén O, M. Gardberg M. Multiple formin proteins participate in glioblastoma migration. BMC Cancer, 20:710, 2020.
Kaipio K, Chen P, Roering P, Huhtinen K, Mikkonen P, Östling P, Lehtinen L, Korpela T, Potdar S, Hynninen J, Auranen A, Grénman S, Wennerberg K, Hautaniemi S and Carpén O. ALDH1A1-related stemness in high-grade serous ovarian cancer is a negative prognostic indicator but potentially targetable by EGFR/mTOR-PI3K/aurora kinase inhibitors. J Pathol. 2020; 250:159-169
Oikkonen J, Zhang K, Salminen L, Schulman I, Lavikka K, Andersson N, Ojanperä E, Hietanen S, Grénman S, Lehtonen R, Huhtinen K, Carpén O, Hynninen J, Färkkilä A and Hautaniemi A. Prospective longitudinal ctDNA workflow reveals clinically actionable alterations in ovarian cancer. JCO Precision Oncology 2019; 3:1-12
Peippo MH, Kurki S, Lassila R, Carpén O. Real-world features associated with cancer-related venous thromboembolic events. ESMO Open. http://dx.doi.org/10.1136/esmoopen-2018-000363, 2018

Description of research

Diffuse large B cell lymphoma (DLBCL) is a highly aggressive and the most common type of all B cell lymphomas and is diagnosed in ~600 patients in Finland each year (Duodecim, 2022). B cell lymphomas of different molecular subtypes are formed when the tightly regulated B cell activation signalling fails. Critical for B cell activity regulation are its various vesicle populations, but their functions in B cell lymphomas is unknown. In our group, we aim to explore the possibility to pharmacologically target lysosomes to attenuate human B lymphoma cell proliferation. We utilise DLBCL cells and patient samples, high-resolution imaging and three-dimensional (3D) tissue models to emulate as much as possible the in vivo organization of surface receptors, local pH levels and drug responses. Furthermore, we investigate the altered phenotype of extracellular vesicles (EVs) in DLBCL, with potential biomarker possibilities to detect B cell lymphomas.

Current topics

The vesicle heterogeneity in human diffuse large B cell lymphoma (DLBCL) subtypes
Lysosome function and pharmacological targeting in DLBCLs
Extracellular vesicle function and characteristics of DLBCLs
Biomarker characterization of DLBCL EVs
3D models of DLBCLs

Research group members

PhD students: Jelena Gnjatovic (MSc), Lujain ALGhadir (MSc)
Master students: Nasir Badal (BSc)
Research assistant: Anni Virtanen (BSc)

Recent key publications

Hämälistö*, S., Stahl-Meyer*, J., Favaro, E., Qing Yang, Bin Liu, Line Christoffersen, Ben Loos, Claudia Guasch Boldu, Johanna A. Joyce, Thomas Reinheckel, Barisic, M., and Jäättelä, M. Spatially and temporally defined lysosomal leakage facilitates mitotic chromosome segregation. Nat Commun. 11:229, 2020. * Equal contribution.
Hämälistö, S., Stahl-Meyer, J., and Jäättelä, M. They Might Cut It—Lysosomes and Autophagy in Mitotic Progression Front. Cell Dev. Biol. 9:727538, 2021.
Corcelle-Termeau E, Vindeløv SD, Hämälistö S, Mograbi B, Keldsbo A, Bräsen JH, Favaro E, Adam D, Szyniarowski P, Hofman P, Krautwald S, Farkas T, Petersen NH, Rohde M, Linkermann A, Jäättelä M. Excess sphingomyelin disturbs ATG9A trafficking and autophagosome closure. Autophagy 12:833-49, 2016.
Aits S, Kricker J, Liu B, Ellegaard AM, Hämälistö S, Tvingsholm S, Corcelle-Termeau E, Høgh S, Farkas T, Holm Jonassen A, Gromova I, Mortensen M, Jäättelä M. Sensitive detection of lysosomal membrane permeabilization by lysosomal galectin puncta assay. Autophagy. 11:1408-24, 2015.
Högnäs, G., Hämälistö, S., Rilla, K., Laine, J., Vilkki, V., Murumägi, A., Edgren, H., Kallioniemi, O. and Ivaska, J. (2013). Aneuploidy facilitates oncogenic transformation via specific genetic alterations, including Twist2 upregulation. Carcinogenesis. 34(9):2000-9.

Description of Research

Our research focuses on tumor stromal interactions in growth and progression of steroid hormone-regulated breast and prostate cancer and in development of hormone resistance. We specifically focus on the mechanisms and functions of the fibroblast growth factor receptor (FGFR) tumor progression and metastasis. Our methods include analysis of human tumor tissues in combination with clinical data, and use of several in vitro and in vivo experimental models.

Current topics

FGFR signaling pathways in breast and prostate cancer: mechanisms and functions
Interactions of androgen receptor and FGFR signaling in prostate cancer
Importance of o-glycosylation for breast and prostate cancer growth in experimental models
Tumor - tumor microenvironment connections in triple negative breast cancer

Research group members

PhD students: Syeda Afshan, Nataliia Petruk, Alejandra Verhassel

Recent key publications

Kähkönen TE, Ivaska KK, Jian M, Büki KG, Väänänen HK, Härkönen PL. Role of fibroblast growth factor receptors (FGFR) and FGFR like-1 (FGFRL1) in mesenchymal stromal cell differentiation to osteoblasts and adipocytes. Mol Cell Endocrinol 461:194-204, 2018
Virtanen SS, Sandholm J, Ishizu T, Löyttyniemi E, Väänänen HK, Tuomela J, Härkönen PL. Alendronate-induced disruption of actin cytoskeleton is associated with cofilin downregulation in PC-3 prostate cancer cells. Oncotarget 9(66):32593-32608, 2018
Kähkönen TE, Tuomela JM, Grönroos T, Ivaska KK, Härkönen PL. Dovitinib dilactic acid (TKI258) reduces tumor growth and tumor-induced bone changes in an experimental breast cancer bone growth model. J Bone Oncol 19;16:100232, 2019
Valta M, Ylä-Pelto J J, Yu L, Kähkönen T, Taimen P, Boström PJ, Ettala O, Khan S, Paulin N, Elo LL, Koskinen PJ, Härkönen P, Tuomela J. Critical evaluation of the subcutaneous engraftments of hormone naïve primary prostate cancer. Translat Androl Urol. In Press 2020
Kähkönen TE, Toriseva M, Petruk N, Virta A-R, Mäntylä A, Eigeliene N, Kaivola J, Boström P, Koskivuo I, Ivaska KK and Härkönen PL. Effects of FGFR inhibitors TKI258, BGJ398 and AZD4547 on breast cancer cells in 2D, 3D and tissue explant cultures. Cellular Oncology, 1-14. DOI. 10.1007/s13402-020-00562-0, 2020

Description of Research

Our aim is to understand the means cancer cells use to develop resistance to cancer therapies. Our special focus are the mechanisms that enable the establishment of minimal residual disease, or govern the maintenance of residual tumors following targeted cancer therapy. The overarching goal of our research is to develop rational combination strategies that will extend the long-term efficacy of clinically used cancer therapies.

Current topics

Mechanisms underlying evasion of apoptosis following targeted therapy
Modulation of tumor immune response by residual cancer cells
Specific vulnerabilities of residual cancer cells as novel therapeutic targets

Research group members

PhD students: Mari Tienhaara, Meija Honkanen
Other students: Kamal Wahid (MSc student)

Recent key publications

Kurppa KJ, Westermarck J. Good Guy in Bad Company: How STRNs Convert PP2A into an Oncoprotein. Cancer Cell. 2020; 38(1):20-22.
Kurppa KJ, Liu Y, To C, Zhang T, Fan M, Vajdi A, Knelson EH, Xie Y, Lim K, Cejas P, Portell A, Lizotte PH, Ficarro SB, Li S, Chen T, Haikala HM, Wang H, Bahcall M, Gao Y, Shalhout S, Boettcher S, Shin BH, Thai T, Wilkens MK, Tillgren ML, Mushajiang M, Xu M, Choi J, Bertram AA, Ebert BL, Beroukhim R, Bandopadhayay P, Awad MM, Gokhale PC, Kirschmeier PT, Marto JA, Camargo FD, Haq R, Paweletz CP, Wong KK, Barbie DA, Long HW, Gray NS, Jänne PA. Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway. Cancer Cell. 2020; 37(1):104-122.e12.
Boettcher S, Miller PG, Sharma R, McConkey M, Leventhal M, Krivtsov A V., Giacomelli AO, Wong W, Kim J, Chao S, Kurppa KJ, Yang X, Milenkowic K, Piccioni F, Root DE, Rücker FG, Flamand Y, Neuberg D, Coleman Lindsley R, Jänne PA, Hahn WC, Jacks T, Döhner H, Armstrong SA, Ebert BL. A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies. Science. 2019; 365(6453):599-604.
Kurppa KJ, Denessiouk K, Johnson MS, Elenius K. Activating ERBB4 mutations in non-small cell lung cancer. Oncogene. 2016; 35(10):1283-91.
Kurppa KJ, Catón J, Morgan PR, Ristimäki A, Ruhin B, Kellokoski J, Elenius K, Heikinheimo K. High frequency of BRAF V600E mutations in ameloblastoma. J Pathol. 2014; 232(5):492-498.

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Ilmo Leivo: New diagnostic and prognostic biomarkers in head and neck cancer

Ilmo Leivo

Matthias Nees: High Content Screening Lab

Matthias Nees

Contact: matthias.nees@utu.fi

Description of Research

At our “High Content Screening Lab” or HCSLab, we use advanced 3D models that faithfully replicate the architecture or histology of solid cancer tissues to study tumour-stroma interactions, epithelial differentiation, and maturation. These models provide the necessary means for predictive in vitro therapy response studies, and personalized medicine. Tissue-like, advanced 3D models also promote the predictive value of early-stage drug discovery studies - for lead discovery and functional drug target validation. For this, we use both cell lines and primary cell cultures extracted from patient biopsies.

Recent key publications

L, Toriseva M, Afshan S, Cangiano M, Fey V, Erickson A, Seikkula H, Alanen K, Taimen P, Ettala O, Nurmi M, Boström PJ, Kallajoki M, Tuomela J, Mirtti T, Beumer IJ, Nees M, Härkönen P. (2022). Increased Expression and Altered Cellular Localization of Fibroblast Growth Factor Receptor-Like 1 (FGFRL1) Are Associated with Prostate Cancer Progression. Cancers (Basel) 14(2):278. doi: 10.3390/cancers14020278.
Desai D, Åkerfelt M, Prabhakar N, Toriseva M, Näreoja T, Zhang J, Nees M, and Rosenholm J (2018). Factors affecting intracellular delivery and release of hydrophilic versus hydrophobic cargo from mesoporous silica nanoparticles on 2D and 3D cell cultures. Pharmaceutics 10(4), 237; https://doi.org/10.3390/ pharmaceutics10040237.
Ahonen I, Åkerfelt M, Toriseva M, Oswald E, Schüler J, Nees M (2017). A high-content image analysis approach for quantitative measurements of chemosensitivity in patient-derived tumour microtissues. Sci. Rep. 7:6600. doi: 10.1038/s41598-017-06544-x.
Åkerfelt, M., Bayramoglu, N., Robinson, S., Toriseva, M., Schukov, H.-P., Virtanen, J., Härmä, V., Kaakinen, M., Kannala, J., Eklund, L., Heikkilä, J., and Nees, M. (2015). Automated tracking of tumor-stroma morphology in microtissues identifies targets within the tumor microenvironment for therapeutic intervention. Oncotarget 6:30035-56. doi: 10.18632/oncotarget.5046.
Robinson, S., Guyon, L., Nevalainen, J., Toriseva, M., Åkerfelt, M., and Nees, M. (2015). Segmentation of Image Data from Complex Organotypic 3D Models of Cancer Tissues with Markov Random Fields. PLoS One. 10:e0143798. doi: 10.1371/journal.pone.0143798.

Description of Research

Pluripotent stem cells are capable of dividing indefinitely and differentiate into all somatic cell types of the human body. Our special focus is to understand the correspondences between the regulation of pluripotency and cancer progression. Our research combines quantitative proteomics, high-resolution genotyping, and sequencing techniques with cutting-edge stem cell and genetic engineering techniques. The ultimate aim is to boost the development of regenerative medicine and cancer therapies.

Current topics

Biomarkers for pluripotency, stem cells, and cancer progression
Detection of stem cells in normal and cancer tissues
Pluripotent oncogenic models
Extracellular pluripotent proteins mediating stemness
Production of patient specific cell lines via reprogramming

Research group members

Postdoctoral researcher: Nikolaos Giannareas
PhD students: Sofia Hakala, Rasha Elmansuri and Sanne Sandelin
Master students: Paula Kuuppo

Recent key publications

Närvä E., Taskinen ME., Lilla S., Isomursu A., Pietilä M., Weltner J., Isola J., Sihto H., Joensuu H., Zanivan S., Norman J., Ivaska J. (2022). MASTL is enriched in cancerous and pluripotent stem cells and influences OCT1/OCT4 levels. iScience May 25; 25(6):104459.
Närvä E, Stubb A, Guzmán C, Blomqvist M, Balboa D, Lerche M, Saari M, Otonkoski T, Ivaska J. (2017) A Strong Contractile Actin Fence and Large Adhesions Direct Human Pluripotent Colony Morphology and Adhesion. Stem Cell Reports Jul 11;9(1):67-76.
Lund R.*, Närvä E.* & Lahesmaa R. (2012) Genetic and Epigenetic stability of human pluripotent stem cells. Nature Reviews Genetics, Oct;13(10):732-44.
Närvä E.*, Rahkonen N.*, Maheswara R.*, Lund R., Pursiheimo J-P., Nästi J., Autio R., Rasool O., Denessiouk K., Lähdesmäki H., Rao A. and Lahesmaa R. (2012) RNA Binding Protein L1TD1 Interacts with LIN28 via RNA and Is Required for Human Embryonic Stem Cell Self-renewal and Cancer Cell Proliferation. STEM CELLS Mar;30(3):452-60
Närvä E., Autio R., Rahkonen N., Kong L., Harrison N., Kitsberg D., Borghese L., Itskovitz-Eldor J., Rasool O., Dvorak P., Hovatta O., Otonkoski T., Tuuri T., Cui W., Brüstle O., Baker D., Maltby E., Moore H. D., Benvenisty N., Andrews P. W., Yli-Harja O. & Lahesmaa R. (2010) High-resolution DNA analysis of Human Embryonic Stem Cell lines reveals culture-induced copy number changes and loss of heterozygosity. Nature Biotechnology Apr;28(4):371-7.

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Juha Peltonen: Cancer syndrome/Rasopathy NF1: pathoetiology and epidemiology

Juha Peltonen, MD PhD, Professor of Anatomy

Contact: juhpel@utu.fi

Description of Research

Mutations of NF1 gene cause the multi organ syndrome neurofibromatosis 1 (NF1) with a birth incidence of about 1:2000. NF1 is also the most common cancer syndrome, and can also be classified as a Rasopathy. Our research penetrates to the question how a single mutation in the NF1 gene can cause the development of tumor masses, skeletal disfigurement, speech defects, and tumors of the optic pathway. We have established the Finnish neurofibromatosis cohort which is total population based and comprehensive. This has enabled the recognition of novel cancer associations in NF1 and that NF1 mutations protect against risk of diabetes.

Current topics

Comorbidity in Rasopathy NF1, including e.g. established protection to diabetes and sugar metabolism
Breast cancer in NF1, which is associated with early onset and poor prognostic factors
An interdisciplinary approach: Coping with rare disease; educational attainment and labor market performance

Research group members

Senior researchers: Sirkku Peltonen, Heli Ylä-Outinen, Eija Martikkala
PhD students: Roope Kallionpää, Pirita Raanta, Maria Alanne, Niina Loponen
Other students: Kim My Le, Sini Viitamäki, Mira Jääskeläinen, Tommi Frang

Recent key publications

Kallionpää R, Peltonen S, Leppävirta J, Pöyhönen M, Auranen K, Järveläinen H, Peltonen J: Haploinsufficiency of the NF1 gene is associated with protection against diabetes. J Med Genet (2020 in press) PMID: 32571896 DOI: 10.1136/jmedgenet-2020-107062
Evans DGR, Kallionpää RA, Clementi M, Trevisson E, Mautner V, Howell SJ, Lewis L, Zehou O, Peltonen S, Brunello A, Harkness EF, Wolkenstein P, Peltonen J: Risk of contralateral breast cancer and survival in neurofibromatosis 1: A five country cohort study. Genet Med. 22:398-406, 2020 doi: 10.1038/s41436-019-0651-6
Ylä-Outinen H, Loponen N, Kallionpää RA, Peltonen S, Peltonen J: Intestinal tumors in neurofibromatosis 1 with special reference to fatal gastrointestinal stromal tumors (GIST). Mol Genet Genomic Med. 2019;e927. https ://doi.org/10.1002/mgg3.927
Uusitalo E, Rantanen M, Kallionpää RA, Pöyhönen M, Leppävirta J, Ylä-Outinen H, Riccardi VM, Pukkala E, Pitkäniemi J, Peltonen S, and Peltonen J: Distinctive cancer associations in patients with Neurofibromatosis 1. J Clin Oncol. 34:1978-1986, 2016
Uusitalo E, Kallionpää RA, Kurki S, Rantanen M, Pitkäniemi J, Kronqvist P, Härkönen P, Huovinen R, Carpen O, Pöyhönen M, Peltonen S and Peltonen J: Breast Cancer in Neurofibromatosis Type 1 (NF1): Overrepresentation of Unfavorable Prognostic Factors. Br J Cancer 116:211-217, 2017. doi: 10.1038/bjc.2016.403

Description of Research

The mechanical properties of cells and their tissue environment have been suggested to contribute to the maintenance of regenerative capacity in normal tissues and in cancer. With primary human breast tissue, we investigate how mechanotransduction ie. the mechanical links between the extracellular environment and the cell interior regulates to breast morphogenesis and malignant transformation. Our research combines organoid culture techniques and gene expression analysis to advanced imagining techniques and quantitative mechanobiology, and aims to decipher the fundamental mechanisms in mammary gland development and to pinpoint novel therapeutic targets for breast cancer.

Current topics

Mechanotransduction in human breast epithelium
Mammary epithelial intermediate filaments
Branching morphogenesis of the human breast
Tissue stiffness in the regulation of breast carcinoma progression

Research group members

Senior researchers: Markus Peurla
PhD students: Defne Dinc, Oona Paavolainen
Other students: Leena Koskinen, Sonja Vahlman, Suvi-Riitta Sulander, Ella Tammelin

Recent key publications

Paavolainen O & Peuhu E: Integrin-mediated adhesion and mechanosensing in the mammary gland. Semin Cell Dev Biol. https://doi.org/10.1016/j.semcdb.2020.10.010, 2020
Lerche M, Elosegui-Artola A, Guzman C, Kechagia J, Georgiadou M, Gullberg D, Roca-Cusachs P, Peuhu E, and Ivaska J: Integrin binding dynamics modulate ligand-specific mechanosensing in mammary gland fibroblasts. iScience. 23(3):100907, 2020.
Laukka M, Hoppela E, Salo J, Rantakari P, Grönroos TJ, Orte K, Auvinen K, Salmi M, Gerke H, Thol K, Peuhu E, Kauhanen S, Merilahti P, and Hartiala P: Preperitoneal Fat Grafting Inhibits the Formation of Intra-abdominal Adhesions in Mice. J Gastrointest Surg. doi: 10.1007/s11605-019-04425-4, 2019.
Peuhu E, Virtakoivu R, Mai A, Wärri A, and Ivaska J: Epithelial vimentin plays a functional role in mammary gland development. Development. 144:4103-4113, 2017.
Peuhu E, Kaukonen R, Lerche M, Saari M, Guzmán C, Rantakari P, De Franceschi N, Wärri A, Georgiadou M, Jacquemet G, Mattila E, Virtakoivu R, Liu Y, Attieh Y, Silva KA, Betz T, Sundberg JP, Salmi M, Deugnier M-A, Eliceiri KW, and Ivaska J: SHARPIN regulates collagen architecture and ductal outgrowth in the developing mouse mammary gland. EMBO J. 36, 165-182, 2017.

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Carlos Rogerio de Figueiredo: Melanoma immune oncology

Carlos Rogerio de Figueiredo, PhD, Docent

Contact: crdefi@utu.fi

Description of Research

Our research aims to improve current cancer immunotherapies by targeting specific biomarkers that are associated with T lymphocytes exclusion from the tumor. Our main cancer model is metastatic cutaneous melanoma, but we also study metastatic uveal melanoma, which is known to be the most refractory cancer to immunotherapies using immune checkpoint inhibitors (ICI). The goal of our research is not only to discover new biomarkers that predict patient response to immunotherapies using ICI, but also to develop new pharmacological strategies that mitigate the resistance mechanisms of these biomarkers to unleash the full power of ICI immunotherapies.

Current topics

Mechanisms underlying resistance to immune checkpoint inhibitors.
Modulation of tumor microenvironment.
Antigen presentation and tumor immunogenicity.

Research group members

PhD students: Eleftheria Maranou, Saara Koskela
Other students: Nesreen Mohamed

Recent key publications

Figueiredo CR, Kalirai H, Sacco JJ, Azevedo RA, Duckworth A, Slupsky JR, Coulson JM, Coupland SE. Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development. (2020) The Journal of Pathology. Apr;250(4):420-439.
Ireland, L., Santos, A., Campbell, F., Figueiredo, C.R, Hammond, D., Ellies, L.G., Weyer-Czernilofsky, U., Bogenrieder, T., Schmid, M., Mielgo, A. Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer (2018) Oncogene, 37 (15), pp. 2022-2036.
Figueiredo, C.R., Azevedo, R.A., Mousdell, S., Resende-Lara, P.T., Ireland, L., Santos, A., Girola, N., Cunha, R.L.O.R., Schmid, M.C., Polonelli, L., Travassos, L.R., Mielgo, A. Blockade of MIF-CD74 signalling on macrophages and dendritic cells restores the antitumour immune response against metastatic melanoma. (2018) Frontiers in Immunology, 9 (MAY), art. no. 112.
Figueiredo, C.R., Matsuo, A.L., Azevedo, R.A., Massaoka, M.H., Girola, N., Polonelli, L., Travassos, L.R. A novel microtubule de-stabilizing complementarity-determining region C36L1 peptide displays antitumor activity against melanoma in vitro and in vivo. (2015) Scientific Reports, 5, art. no. 14310.
Matsuo, A.L., Juliano, M.A., Figueiredo, C.R., Batista, W.L., Tanaka, A.S., Travassos, L.R. A new phage- display tumor-homing peptide fused to antiangiogenic peptide generates a novel bioactive molecule with antimelanoma activity. (2011) Molecular Cancer Research, 9 (11), pp. 1471-1478.

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Pekka Ruusuvuori: Bioimage informatics

Pekka Ruusuvuori, DSc(Tech), Assistant Professor of Bioimage Informatics

Contact: pekka.ruusuvuori@utu.fi

Description of Research

‘Bioimage informatics and predictive biomedicine’ research group develops computational methods for data-intensive applications in biomedical sciences. Our research focuses on method development for computational pathology and cancer research, where our goal is to develop AI-based diagnostic tools and decision support systems. We are actively studying AI-based image interpretation and predictive analytics also in several other application areas in biomedicine both in clinical and pre-clinical stage. We are also developing computational tools for multimodal data analysis and visualization of large-scale biomedical data. Our research provides state-of-the-art technical solutions for cancer research, and our work has translational potential in routine clinical work.

Current topics

Computational pathology for enhanced diagnostics patient stratification
3D histology: reconstruction, visualization and quantitative spatial analysis of tissue on organ level
Advancing Breast Cancer histopathology towards AI-based Personalised medicine (ABCAP)
Reprogramming of macrophage phenotypes as early predictor of cardiovascular and metabolic disease development (MAP-CAD)

Research group members

Senior researchers: Kimmo Kartasalo (KI)
PhD students: Masi Valkonen, Umair Akhtar; Mira Valkonen, Kaisa Liimatainen (TUNI)
Other students: Hannu Hakkola

Recent key publications

Ström, Peter, et al. "Artificial intelligence for diagnosis and grading of prostate cancer in biopsies: a population-based, diagnostic study." The Lancet Oncology 21.2 (2020): 222-232. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30738-7/fulltext
Valkonen, M., Isola, J., Ylinen, O., Muhonen, V., Saxlin, A., Tolonen, T., ... & Ruusuvuori, P. (2019). Cytokeratin-Supervised Deep Learning for Automatic Recognition of Epithelial Cells in Breast Cancers Stained for ER, PR, and Ki-67. IEEE Transactions on Medical Imaging, 39(2), 534-542. https://ieeexplore.ieee.org/abstract/document/8790728
Liimatainen, K., Kananen, L., Latonen, L., & Ruusuvuori, P. (2019). Iterative unsupervised domain adaptation for generalized cell detection from brightfield z-stacks. BMC bioinformatics, 20(1), 1-10. https://bmcbioinformatics.biomedcentral.com/articles/10.1186/s12859-019-2605-z
Kartasalo, K., Latonen, L., Vihinen, J., Visakorpi, T., Nykter, M., & Ruusuvuori, P. (2018). Comparative analysis of tissue reconstruction algorithms for 3D histology. Bioinformatics, 34(17), 3013-3021. https://academic.oup.com/bioinformatics/article/34/17/3013/497804
Valkonen, M., Ruusuvuori, P., Kartasalo, K., Nykter, M., Visakorpi, T., & Latonen, L. (2017). Analysis of spatial heterogeneity in normal epithelium and preneoplastic alterations in mouse prostate tumor models. Scientific reports, 7, 44831. https://www.nature.com/articles/srep44831

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Johanna Schleutker: Genetic predisposition to cancer

Johanna Schleutker, PhD, Professor of Medical Genetics

Contact: johanna.schleutker@utu.fi

Description of Research

We study genetic predisposition to prostate (PrCa) and breast (BrCa) cancer. Our goal is to characterize and explain mechanistic roles of the genetically predisposing gene variants, both in coding and non-coding genomic regions. The focus of our strategy is in contrasting patients with more and less aggressive disease, and exploring variants associated with disease progression and prognosis. Special interest is in aggressive and castration resistant prostate cancer (CRPC) and in BRCA1/2 negative, early-onset BrCa, with patients of strong family history of the disease. All work is based on powerful synergistic combination of the unique genomic and clinical data, efficient collaboration networks, and sophisticated data analyses.

Current topics

Functional studies of ANO7 and HOXB13 PrCa risk genes
Characterization of the genomic PrCa risk regions at 2q37.3 and 17q21-22
Risk genes of BRCA1/2 negative early onset BrCa cases

Research group members

Senior researchers: Gudrun Wahlström, Christoffer Löf, Neha Goel and Vidal Fey
PhD students: Olli Metsälä, Viivi Laitinen, Nasrin Sultana, Venkat Rathinakannan, Dhanaprakash Jambulingam
Other students: Tuuli Levänen, Anni Orava
Technicians: Jukka Karhu

Recent key publications

Wahlström G, Heron S, Knuuttila M, Kaikkonen E, Tulonen N, Metsälä O, Löf C, Ettala O, Boström PJ, Taimen P, Poutanen M, Schleutker J. The variant rs77559646 associated with aggressive prostate cancer disrupts AN07 mRNA splicing and protein expression. Hum Mol Genet, 31(12):2063-2077, 2022.
Sipeky C, Talala KM, Tammela TLJ, Taari K, Auvinen A, Schleutker J. Prostate cancer risk prediction using a polygenic risk score. Sci Rep 10(1):17075, 2020.
Gao P, Xia JH, Sipeky C, Dong XM, Zhang Q, Yang Y, Zhang P, Cruz SP, Zhang K, Zhu J, Lee HM, Suleman S, Giannareas N, Liu S; PRACTICAL Consortium, Tammela TLJ, Auvinen A, Wang X, Huang Q, Wang L, Manninen A, Vaarala MH, Wang L, Schleutker J, Wei GH. Biology and Clinical Implications of the 19q13 Aggressive Prostate Cancer Susceptibility Locus. Cell, 174(3):576-589, 2018.
Kaikkonen E, Rantapero T, Zhang Q, Taimen P, Laitinen V, Kallajoki M, Jambulingam D, Ettala O, Knaapila J, Boström PJ, Wahlström G, Sipeky C, Pursiheimo J-P, Tammela T, Kellokumpu-Lehtinen P-L, PRACTICAL Consortium, Fey V, Maehle L, Wiklund F, Wei G-H, Schleutker J. ANO7 is associated with aggressive prostate cancer. Int J Cancer, 143(10):2479-2487, 2018.
Sipeky C, Gao P, Zhang Q, Wang L, Ettala O, Talala KM, Tammela TLJ, Auvinen A, PRACTICAL Consortium, Wiklund F, Wei G-H, Schleutker J. Synergistic interaction of HOXB13 and CIP2A predispose to aggressive prostate cancer. Clin Cancer Res, 24(24):6265-6276, 2018.

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Maria Sundvall: DNA Repair Pathways in Prostate Cancer

Maria Sundvall, MD PhD, Adjunct Professor in Medical Biochemistry and Molecular Biology, Clinical Lecturer and Consultant in Clinical Oncology

Contact: mahesu@utu.fi

Description of Research

We study the relevance of DNA damage repair (DDR) and SUMO pathways in cancer. Up to 30 % of tumors in patients with lethal castration resistant prostate cancer carry mutations in DDR genes. One of our goals is to understand the functional relevance of DDR pathways in prostate cancer and their involvement in response to current therapies. The function of proteins is regulated by posttranslational modifications, such as SUMOylation. DDR and SUMO pathways are also interconnected. Our second goal is to study prognostic role and therapeutic targeting of SUMO pathway in different cancers, such as head and neck cancer and melanoma. We develop and use model systems representing certain subgroups of patients and aim to pave the way for more successful precision medicine.

Current topics

Characterization of new mechanisms in castration resistant prostate cancer
Functional role and new molecular mechanisms regulated by BRCA1 and BRCA2 in prostate cancer
SUMOylation in cancer

Research group members

PhD students: Anniina Hyväkkä, Antti Kukkula, Kreetta Paunu, Emmi Kuokkanen, Saiganesh Sriraman, Verneri Virtanen
Second PhD supervisor: Tamiko Ishizu, Saara Koskela, Sakari Kosola, Sanni Tuominen
Other students: Milla Hollmen, Aathavan Kandiah, Anni Lumiainen, Saana Niva, Janita Sulonen, Pauli Toivanen

Recent key publications

Tuominen S, Nissi L, Kukkula A, Routila J, Huusko T, Leivo I, Minn H, Irjala H, Löyttyniemi E, Ventelä S, *Sundvall M and *Grönroos T. TSPO is a pontetial independent prognostic factor associated with cellular respiration and p16 in head and neck squamous cell carcinoma. Frontiers in Oncology, 13, 2023. *co-last authors.
Virtanen V, Paunu K, Kukkula A, Niva S, Junila Y, Toriseva M, Jokilehto T, Mäkelä S, Huhtaniemi R, Poutanen M, Paatero I, Sundvall M. Glucocorticoid receptor-induced non-muscle caldesmon regulates metastasis in castration-resistant prostate cancer. Oncogenesis, 12: 42. doi: 10.1038/s41389-023-00485-z, 2023.
Virtanen V, Paunu K, Niva S, *Sundvall M, *Paatero I. Effect of caldesmon mutations in the development of zebrafish embryos. Biochemical and biophysical research communications, 669: 10-18, doi: 10.1016/j.bbrc.2023.05.079, 2023. *co-last authors.
Hyväkkä A, Kääriäinen OS, Utriainen T, Löyttyniemi E, Mattila K, Reinikainen P, Sormunen J, Jääskeläinen M, Auvinen P, Minn H and Sundvall M. Radium-223 dichloride treatment in metastatic castration resistant prostate cancer in Finland: A real-world evidence (RWE) multicenter study. Cancer Medicine, 26, 10.1002/cam4.5262, 2023.
Knittle AM, Helkkula M, Johnson MS, *Sundvall M and *Elenius K. Sumoylation regulates nuclear accumulation and signaling activity of the soluble intracellular domain of the erbB4 receptor tyrosine kinase. Journal of Biological Chemistry. 292(48): 19890-904, doi: 10.1074/jbc.M117.794271, 2017. *co-last author

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Pekka Taimen: Nuclear Lamins and Human Disease

Pekka Taimen, MD PhD, Associate Professor in Molecular Pathology and Chief Pathologist

Contact: pekka.taimen@utu.fi

Description of Research

Our translational pathology -oriented research team focuses on pathogenesis, biomarkers and patient-derived cell culture models of prostate, bladder and lung cancer. Additionally, we study the pathobiology of inherited diseases caused by LMNA-mutations, such as dilated cardiomyopathy and premature aging syndrome (progeria). Together with Auria Biobank and the Turku Prostate Cancer Consortium, we are prospectively collecting specimens for research purposes from urological cancers operated at the Turku University Hospital. Using cell culture models, biochemistry, immunohistochemistry, as well as tumor genetics and transgenic animal models we aim for an improved understanding of disease mechanisms and for precision diagnostics.

Current topics

Personalized drug sensitivity screening for bladder cancer using conditionally reprogrammed patient-derived cells
Histologic and radiomic features of clinically significant prostate cancer
Pathobiology of familial dilated cardiomyopathy caused by lamin mutations
Genetics of non-small cell lung cancer in the Finnish population

Research group members

Senior researchers: Gun West, Song-Ping Li, Tarja Lamminen
PhD students: Laura Virtanen, Kimmo Kettunen, Fanny Sundqvist, Irena Saarinen, Eva-Maria Talvitie
Other students: Achol Bhowmik, Lauri Eklund

Recent key publications

Talvitie E-M, Vilhonen H, Kurki S, Karlsson A, Orte K, Almangush A, Mohamed H, Liljeroos L, Singh Y, Leivo I, Laitinen T, Kallajoki M and Taimen P. High tumor mutation burden predicts favorable outcome among patients with aggressive histological subtypes of lung adenocarcinoma: A population-based single-institution study. Neoplasia. 22:333-342, 2020.
Kettunen K, Boström PJ, Lamminen T, Heinosalo T, West G, Saarinen I, Kaipio K, Rantala J, Albanese C, Poutanen M, Taimen P. Personalized Drug Sensitivity Screening for Bladder Cancer Using Conditionally Reprogrammed Patient-derived Cells. Eur. Urol. 76:430-434, 2019.
Shah D, Virtanen L, Prajapati C, Kiamehr M, Gullmets J, West G, Kreutzer J, Pekkanen-Mattila M, Heliö T, Kallio P, Taimen P*, Aalto-Setälä K*. Modeling of LMNA-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells. Cells 8:pii: E594, 2019.
Merisaari H, Jambor I, Ettala O, Boström PJ, Montoya Perez I, Verho J, Kiviniemi A, Syvänen K, Kähkönen E, Eklund L, Pahikkala T, Vainio P, Saunavaara J, Aronen HJ, Taimen P. IMPROD biparametric MRI in men with a clinical suspicion of prostate cancer (IMPROD Trial): Sensitivity for prostate cancer detection in correlation with whole-mount prostatectomy sections and implications for focal therapy. J. Magn. Reson. Imag. 50:1641-1650, 2019.
West G, Gullmets J, Virtanen L, Li SP, Keinänen A, Shimi T, Mauermann M, Heliö T, Kaartinen M, Ollila L, Kuusisto J, Eriksson JE, Goldman RD, Herrmann H, Taimen P. Deleterious assembly of the lamin A/C mutant p.S143P causes ER stress in familial dilated cardiomyopathy. Journal of Cell Science 129:2732-43, 2016.

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Jukka Westermarck: Cancer Cell Signaling

Jukka Westermarck, Professor of Cancer Biology, Research director

Contact: jukka.westermarck@utu.fi

Description of Research

Our group studies mechanisms that are related to the development of cancer and resistance to cancer therapies. Our focus is to understand the role and regulation of Protein phosphatase 2A (PP2A) in human cancers and especially function of PP2A inhibitor proteins as human oncoproteins. Our recent results suggest that a potential biological outcome of aberrant PP2A signaling in cancer is conferring drug resistance. We hypothesize that re-activation of PP2A, via targeting of its endogenous inhibitory proteins, could be used as a general strategy for multi-target inhibition of chemoresistance in common human cancer types. In addition, these results may have importance in patient stratification for monotherapies using the identified small molecule compounds.

Current topics

Deregulated phosphatases in human breast cancer Despite of huge advancements on breast cancer therapy, certain breast cancer subtypes still lack any targeted therapies, or develop resistance to existing therapies. Leveraging on yet uncapitalized potential of phosphatases as breast cancer tumor suppressors and oncoproteins, we have several ongoing projects to address the relevance of phosphatase-mediated phosphoregulation in human breast cancer development and in therapy resistance.
Reactivation of PP2A for malignant brain tumors Glioblastoma (GBM) is a fatal disease in which all oncogene-targeted therapies have thus far failed. GBM therapies are also complicated by challenges related to poor blood-brain barrier permeability which limits many otherwise effective therapies. Protein phosphatase 2A (PP2A) is inhibited in GBM by non-genetic mechanisms and is thus amendable for reactivation. In addition, we have recently demonstrated that combination of PP2A reactivation and multikinase inhibition results in profound synergistic cell killing of human glioma cells in vitro and in vivo.
PP2A-mediated control of epigenetics and gene expression Epigenetic complexes are known to be critically involved in cancer initiation and progression. However, it is very poorly understood how functions of epigenetic complexes and gene expression mechanisms are regulated via phosphorylation-dependent signaling. Our recent results indicate a pivotal role for PP2A in determining phosphorylation of several key epigenetic complex components and in various steps of gene expression.
CIP2A structure-function analysis CIP2A is an oncogenic PP2A inhibitor protein overexpressed in most human cancer types. CIP2A inhibition effectively limits tumor growth both in xenograft and knock-out mouse models. Transgenic CIP2A overexpression also induces Alzheimer´s disease phenotypes in mouse brain and behavioural changes typical for Alzheimer´s disease onset. Together these characteristics make CIP2A as a very attractive drug target protein. Thereby, we are currently focusing on understanding of molecular mechanisms of CIP2A-mediated PP2A inhibition and characterization of potential druggability of CIP2A.

Research group members

Senior researchers: Julia Vainonen
Post docs: Anna Aakula, Oxana Denisova, Nikhil Gupta, Riikka Huhtaniemi, Majid Momeny
PhD students: Umar Butt, Joni Merisaari, Eleonora Mäkelä, Srikar Nagelli, Mukund Sharma
Other students: Aleksi Lehtinen, Mari Tienhaara
Laboratory manager: Tiina Arsiola
Technicians: Taina Kalevo-Mattila

Recent key publications

Kauko O, Imanishi SY, Kulesskiy E, Yetukuri L, Laajala TD, Sharma M, Pavic K, Aakula A, Rupp C, Jumppanen M, Haapaniemi P, Ruan L, Yadav B, Suni V, Varila T, Corthals GL, Reimand J, Wennerberg K, Aittokallio T, Westermarck J; Phosphoproteome and drug response effects mediated by the three Protein Phosphatase 2A inhibitor proteins CIP2A, SET and PME-1. J Biol Chem. 2020 Feb 18.
Kauko O, O’Connor KM, Kulesskiy E, Sangodkar J, Aakula A, Izadmehr S, Yetukuri L, Yadav B, Padzik A, Laajala TD, Haapaniemi P, Momeny M, Varila T, Ohlmeyer M, Aittokallio T, Wennerberg K, Narla G, and Westermarck J; PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells. Sci Transl Med. 2018 Jul 18;10(450)
Wang J, Okkeri J, Pavic K, Wang Z, Kauko O, Halonen T, Sarek G, Ojala PM, Rao Z, Xu W, Westermarck J; Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56. EMBO Rep. 2017 Mar.18(3:437-450
Kaur A, Denisova O, Qiao X, Jumppanen M, Peuhu E, Ahmed SU, Raheem O, Haapasalo HK, Eriksson J, Chalmers AJ, Laakkonen PM, Westermarck J; PP2A inhibitor PME-1 drives kinase inhibitor resistance in glioma cells. Cancer Res. 2016 Sep 26
Laine A, Sihto H, Come C, Rosenfeldt MT, Zwolinska A, Niemelä M, Khanna A, Chan EK, Kähäri VM, Kellokumpu-Lehtinen PL, Sansom OJ, Evan GI, Junttila MR, Ryan KM, Marine JC, Joensuu H, Westermarck J. Senescence sensitivity of breast cancer cells is defined by positive feedback loop between CIP2A and E2F1. Cancer Discov. 2013 Jan 10;3(2):182-97