Wennerberg Group – University of Copenhagen

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Wennerberg Group

Using a chemical systems biology approach, our group aims to functionally and therapeutically stratify cancers, to identify the underlying signals that drive them, how this relates to their molecular features and how effective personalized drug combinations can be predicted and established. To accomplish this, we use high throughput approaches to study primary and early passage cancer cells and their drug responses and relate that to their molecular characteristics. Most cancers are highly heterogeneous both on a phenotypic and genetic level and we therefore focus our studies on single cell analyses where we follow drug responses of different cancer cell subpopulations as well as how the microenvironment and the plasticity of the cells affect drug sensitivity and -resistance. Our research focus is currently on acute myeloid leukemia and high-grade serous ovarian carcinoma. They are diseases where relatively effective first line therapies exist, but where drug resistance very frequently occurs over time. Therefore, these diseases have a very poor long-term prognosis and although they are molecularly well-defined, there is a great unmet need to functionally understand them.

Targeting cancer stem cells

In acute myeloid leukemia, leukemic stem cell populations drive the disease, its phenotype and its heterogeneity. These leukemic/cancer stem cells are inherently resistant to most cancer therapies and immunoevasive and are therefore thought to be the underlying cause of relapses and drug resistance. We are aiming at understanding the phenotypes of the cell of origin and therefore leukemic stem cells in different acute myeloid leukemias and to identify therapies that can target these cells with the hope that these can be turned into curative therapies.

Identifying and understanding drug resistance

Development of drug resistance are major clinical challenges in both acute myeloid leukemia and ovarian cancer and the mechanisms of drug resistance are still poorly understood. By studying the evolution of cancer cells at the single cell level both from serial clinical samples during disease progression and from in vitro generated resistant cell populations, we are aiming to understand the cell states and phenotypes that can confer therapeutic resistance and ultimately how these cell states can be modulated to prevent development of drug resistance in a cancer.

Understanding the role of the microenvironment in targeting cancer cells

The microenvironment in which a cancer cell is in can greatly affect how it responds to drugs, meaning that in vitro and animal models of drug sensitivity testing can be misleading where resistance-promoting microenvironments in our bodies can allow for cancer cells to evade therapy. We are therefore exploring how the microenvironment in the form of nutrients, growth factors/cytokines and other cell types affects cancer cell drug responses in vitro with the goal to understand microenvironmental factors that affect drug responses and ultimately how the can be selectively targeted or bypassed.

Selected recent publications

Tang, J., Zia-ur-Rheman, T., Ravikumar, B., Alam, Z., Rebane, A., Vähä-koskela, M., Peddinti, G., van Adrichem, A.J., Wakkinen, J., Jaiswal, A., Karjalainen, E., Gautam, P., He, L., Parri, E., Khan, S., Gupta, A., Ali, M., Yetukuri, L., Gustavsson, A., Seashore-Ludlow, B., Hersey, A., Leach, A.R., Overington, J.P., Repasky, G., Wennerberg, K. and Aittokallio, T. (2018) DrugTargetCommons: a community-effort to build a consensus knowledgebase for drug-target interactions. Cell Chem. Biol. 25: 224-229

Mpindi JP, Yadav B, Östling P, Gautam P, Malani D, Murumägi A, Hirasawa A, Kangaspeska S, Wennerberg K, Kallioniemi O, Aittokallio T. (2016) Consistency in drug response profiling. Nature. 540:E5-E6

Gautam P, Karhinen L, Szwajda A, Jha SK, Yadav B, Aittokallio T, Wennerberg K. (2016) Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells. Mol. Cancer. 15:34.

Kulesskiy E, Saarela J, Turunen L, Wennerberg K.(2016) Precision Cancer Medicine in the Acoustic Dispensing Era: Ex Vivo Primary Cell Drug Sensitivity Testing. J. Lab. Autom. 21:27-36.

Pemovska T, Johnson E, Kontro M, Repasky GA, Chen J, Wells P, Cronin CN, McTigue M, Kallioniemi O, Porkka K, Murray BW, & Wennerberg K (2015) Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation. Nature. 519:102-105.

Szwajda A, Gautam P, Karhinen L, Jha SK, Saarela J, Shakyawar S, Turunen L, Yadav B, Tang J, Wennerberg K, Aittokallio T. (2015) Systematic Mapping of Kinase Addiction Combinations in Breast Cancer Cells by Integrating Drug Sensitivity and Selectivity Profiles. Chem. Biol. 22:1144-1155

Pemovska T, Kontro M, Yadav B, Edgren H, Eldfors S, Szwajda A, Almusa H, Bespalov MM, Ellonen P, Elonen E, Gjertsen BT, Karjalainen R, Kulesskiy E, Lagstrom S, Lehto A, Lepisto M, Lundan T, Majumder MM, Lopez Marti JM, Mattila P, Murumägi A, Mustjoki S, Palva A, Parsons A, Pirttinen T, Ramet ME, Suvela M, Turunen L, Västrik I, Wolf M, Knowles J, Aittokallio T, Heckman CA, Porkka K, Kallioniemi O, & Wennerberg K (2013) Individualized Systems Medicine strategy to tailor treatments for patients with chemorefractory acute myeloid leukemia. Cancer Discov. 3:1416-1429.