Precision oncology in ovarian cancer

Almost one-third of humans are affected by cancer. This is a complex disease characterized by extreme genetic instability and dynamic evolution. It's important to understand that a multifaceted approach is often necessary to improve the chances of a successful treatment. Precision oncology means that we gain a much finer understanding of an individual’s cancer and we tailor the treatment based on this.
DU Lab
Precision oncology in ovarian cancer; DU Lab

Research group information

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Research group description

The Wnt pathway is a complex signaling cascade that is involved in the regulation of cell growth, differentiation, and survival. Canonical Wnt pathway, also known as the β-catenin-dependent pathway, controls cell proliferation, differentiation, and survival. The non-canonical Wnt signaling, also known as the β-catenin-independent pathway, plays important roles in cell migration, cell polarity, cytoskeletal organization, and cell fate determination.

ROR1/ROR2 and PTK7 are also known as Wnt-binding receptor pseudokinases. They are called pseudokinases because, although they contain kinase domains, they lack the catalytic activity of traditional protein kinases. Instead, they act as scaffold proteins that can recruit and activate other signaling proteins. It has been shown that ROR1 and ROR2 are overexpressed in several types of cancer and are considered as potential therapeutic targets for cancer treatment. Studies have shown that targeting ROR1 and ROR2 can inhibit cancer cell migration and invasion, and reduce the tumorigenicity of cancer cells by inhibiting the non-canonical Wnt signaling pathway. Both ROR1 and ROR2 have been shown to play a role in the regulation of cancer stem cells (CSCs) by activating the non-canonical Wnt signaling pathway to promote self-renewal, proliferation, survival and drug resistance.

Our research focuses on the molecular mechanisms employed by Wnt-binding receptor pseudokinases such as ROR1, ROR2 and PTK7 to promote cell growth and differentiation. We are interested to understand how these receptors signal and how their dysregulated activation leads to tumor development.

Drug resistance is one of the most challenging problem facing cancer treatments today. The intrinsic drug resistance can occur when cancer cells undergo molecular changes that make them insensitive to a particular drug before treatment even begins. In cases of acquired resistance, cancer cells may adapt to the drug while it is being administered, acquiring molecular changes that allow them to escape its effects. The molecular mechanisms that contribute to drug resistance include mutation of the drug's molecular target, changes in the way the drug interacts with the tumor, broad cellular changes, and changes in the tumor microenvironment, among others.

Another research area of high interest for us is to understand how cancer cells respond to drug treatments at single cell level. We aim to uncover cell-specific gene expression signatures that could provide more insights into drug response mechanisms and advance the power of precision oncology.

Research group members

  • Harlan Barker is a postdoctoral researcher at University of Oulu and currently a visiting researcher at FIMM, University of Helsinki. Harlan is interested in improving our understanding of vertebrate gene regulatory mechanisms and, in particular, identifying variation in regulatory regions between modern and ancient humans. Currently, he is developing novel pipelines for analysis of single-cell RNA-Seq data in the analysis of prostate and ovarian cancer samples.
  • Alice Dini is a doctoral researcher at the University of Oulu, Fibrobesity Program. She utilizes both bioinformatics and wet-lab techniques to study drug resistance in cancer cells via multiplexed single-cell RNA sequencing (scRNA-seq). Alice is also involved in other collaborative projects aimed at discovering new drug vulnerabilities in various types of cancer. She has a background in Medical Epigenomics and Genomics.
  • Emilia Piki is a doctoral researcher at University of Oulu and a visiting researcher at FIMM, University of Helsinki. She has a background in Cell and Developmental Biology. Emilia is interested in understanding drug-response phenotypes in ovarian cancer and to develop reliable methodologies and ex-vivo models for translational/preclinical drug-research.
  • Juuli Raivola is Academy of Finland postdoctoral fellow at the University of Helsinki. Her research is focused on understanding the molecular mechanisms associated with drug-resistance in ovarian cancer and uterine leiomyomas. Additionally, Juuli is also involved in collaborative projects investigating the role of non-canonical Wnt-signaling in tumor development and drug-resistance.
  • Frida Rantanen is a bioinformatics research assistant at the university of Oulu, and a visiting researcher at FIMM, University of Helsinki. Her research is focused on understanding the mechanisms of drug resistance in prostate cancer cells and cancer-associated fibroblasts using single-cell RNA sequencing analysis. She has a background in molecular biology and bioinformatics.
  • Subodh Sharma is a postdoctoral researcher at University of Oulu, Fibrobesity Program. Subodh's research is mainly focused on understanding the underlying mechanisms behind the obesity-mediated cancer progression. His main objective is to develop a common 3D model where omental adipocytes interact with cancer cells, characterize molecular profiles, and identify the principal mechanism that favors cancer development.

Relevant publications

Drug response profiles in patient-derived cancer cells across histological subtypes of ovarian cancer: real-time therapy tailoring for a patient with low-grade serous carcinoma. Murumägi A, Ungureanu D, Khan S, Arjama M, Välimäki K, Ianevski A, Ianevski P, Bergström R, Dini A, Kanerva A, Koivisto-Korander R, Tapper J, Lassus H, Loukovaara M, Mägi A, Hirasawa A, Aoki D, Pietiäinen V, Pellinen T, Bützow R, Aittokallio T, Kallioniemi O. Br J Cancer. 2023 PMID: 36476658

Multiomics characterization implicates PTK7 in ovarian cancer EMT and cell plasticity and offers strategies for therapeutic intervention. Raivola J, Dini A, Karvonen H, Piki E, Salokas K, Niininen W, Kaleva L, Zhang K, Arjama M, Gudoityte G, Seashore-Ludlow B, Varjosalo M, Kallioniemi O, Hautaniemi S, Murumägi A, Ungureanu D. Cell Death Dis. 2022 . PMID: 35977930

New insights into the molecular mechanisms of ROR1, ROR2, and PTK7 signaling from the proteomics and pharmacological modulation of ROR1 interactome. Raivola J, Dini A, Salokas K, Karvonen H, Niininen W, Piki E, Varjosalo M, Ungureanu D. Cell Mol Life Sci. 2022 PMID: 35504983

Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases. Sheetz JB, Mathea S, Karvonen H, Malhotra K, Chatterjee D, Niininen W, Perttilä R, Preuss F, Suresh K, Stayrook SE, Tsutsui Y, Radhakrishnan R, Ungureanu D*, Knapp S*, Lemmon MA*. Mol Cell. 2020 . PMID: 32619402 (*equal corresponding authors)

Glucocorticoids induce differentiation and chemoresistance in ovarian cancer by promoting ROR1-mediated stemness. Karvonen H, Arjama M, Kaleva L, Niininen W, Barker H, Koivisto-Korander R, Tapper J, Pakarinen P, Lassus H, Loukovaara M, Bützow R, Kallioniemi O, Murumägi A, Ungureanu D. Cell Death Dis. 2020 PMID: 32989221

Wnt5a and ROR1 activate non-canonical Wnt signaling via RhoA in TCF3-PBX1 acute lymphoblastic leukemia and highlight new treatment strategies via Bcl-2 co-targeting. Karvonen H, Perttilä R, Niininen W, Hautanen V, Barker H, Murumägi A, Heckman CA, Ungureanu D. Oncogene. 2019 PMID: 30631148

Crosstalk between ROR1 and BCR pathways defines novel treatment strategies in mantle cell lymphoma. Karvonen H, Chiron D, Niininen W, Ek S, Jerkeman M, Moradi E, Nykter M, Heckman CA, Kallioniemi O, Murumägi A, Ungureanu D. Blood Adv. 2017. PMID: 29296874

Interaction between ROR1 and MuSK activation complex in myogenic cells. Karvonen H, Summala K, Niininen W, Barker HR, Ungureanu D. FEBS Lett. 2018 PMID: 29292499

ATP binding to the pseudokinase domain of JAK2 is critical for pathogenic activation. Hammarén HM, Ungureanu D, Grisouard J, Skoda RC, Hubbard SR, Silvennoinen O. Proc Natl Acad Sci U S A. 2015 PMID: 25825724

Molecular basis for pseudokinase-dependent autoinhibition of JAK2 tyrosine kinase. Shan Y, Gnanasambandan K, Ungureanu D, Kim ET, Hammarén H, Yamashita K, Silvennoinen O, Shaw DE, Hubbard SR. Nat Struct Mol Biol. 2014 PMID: 24918548

Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F. Bandaranayake RM, Ungureanu D, Shan Y, Shaw DE, Silvennoinen O, Hubbard SR. Nat Struct Mol Biol. 2012 PMID: 22820988

The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling. Ungureanu D, Wu J, Pekkala T, Niranjan Y, Young C, Jensen ON, Xu CF, Neubert TA, Skoda RC, Hubbard SR, Silvennoinen O. Nat Struct Mol Biol. 2011 PMID: 21841788