Margareta Wilhelm Group

Mechanisms regulating tumor development and tumor microenvironment

Tumor development is not only dependent on cell intrinsic activation of proliferation and inhibition of senescence and/or apoptosis. It is becoming increasingly clear that tumor initiation, progression, and response to therapy is dependent on a continuous cross talk between tumor cells, the surrounding stroma and infiltrating immune cells. As tumors increase in size the availability of oxygen and nutrients decrease, which leads to metabolic changes and cellular adaptation. Interestingly, it has been shown that it is in the hypoxic areas within tumors the most malignant cells arise. These cells are often resistant to therapy due to intracellular changes as well as being surrounded by a resistant environment. It is important to understand the mechanisms controlling tumor development in order for us to successfully develop therapies against cancer.


The tumor microenvironment creates a permissive niche that allows for tumor growth and spread. The Wilhelm lab is studying both cell intrinsic and extrinsic mechanisms important for tumor progression.

We are specifically interested in how the p73 gene regulates tumor development. p73 belongs to the p53-family of proteins that act as master regulators of cellular life and death decisions and their functions are impaired or altered during tumor development.  The p73 gene encodes for full-length proteins that act as transcription factors and tumor suppressors (TAp73) and N-terminally truncated dominant negative isoforms that act as oncogenes (DNp73).  We have previously shown that p73 regulates genomic stability, apoptosis, responses to hypoxia, angiogenesis, and drug resistance mechanisms. Building on our findings we are now studying mechanisms important for regulating tumor bioenergetics, tumor-stroma interactions and infiltration of tumor-associated immune cells.

Reprogrammed human stem cells as a model for cancer development

During the past decades, we have seen a virtual explosion in molecularly targeted cancer therapy, with the development of monoclonal antibodies and small molecules targeting specific pathways that have gone awry in cancer cells. However, despite all efforts, targeted cancer therapies have often failed to be effective in large patient populations, with low clinical response rate followed by the emergence of drug resistance. This shows the need for developing new models based on disease-relevant human cells to identify the right biomarkers useful for treatment. Most human cancer cell models used to date are based on immortalized cancer cell lines that poorly reflect the diversity in molecular subclones that exist within each tumor. To overcome this problem, we together with our collaborators, are developing more accurate cancer models that are based on human disease-relevant cells derived by using cellular reprogramming techniques.


Fibroblasts from cancer patients carrying familial cancer predisposition mutations are used for reprogramming into iPS cells and further differentiated into relevant cell type.

Vacancies

The Wilhelm lab is currently recruiting Postdocs, please apply using contact information below. Open positions for Doctoral students are posted on KI homepage when available.

Contact

Research group leader Associate Professor Margareta Wilhelm

Senior researcher

Margareta Wilhelm

Phone: +46-(0)8-524 874 74
Organizational unit: Margareta Wilhelm group
E-mail: Margareta.Wilhelm@ki.se

Group members

Ana Marin NavarroAssociated

ana.marin.navarro@ki.se

Marina StanticAssistant professor

marina.stantic@ki.se

Margareta WilhelmSenior researcher

Margareta.Wilhelm@ki.se

08-524 874 74

Johanna WolfsbergerPhD student, Graduate Student

johanna.wolfsberger@ki.se

LEILEI ZHOUPhD student

leilei.zhou@ki.se

Veronica ZubillagaPostdoc

veronica.zubillaga@ki.se

Niek van BreeAssociated

niek.van.bree@ki.se

Selected Publications:

Generation of induced pluripotent stem cell lines from two Neuroblastoma patients carrying a germline ALK R1275Q mutation.
Marin Navarro A, Day K, Kogner P, Wilhelm M, Falk A
Stem Cell Res 2019 Jan;34():101356

Modeling cancer using patient-derived induced pluripotent stem cells to understand development of childhood malignancies.
Marin Navarro A, Susanto E, Falk A, Wilhelm M
Cell Death Discov 2018 Dec;4():7

ΔNp73 enhances HIF-1α protein stability through repression of the ECV complex.
Stantic M, Wolfsberger J, Sakil H, Wilhelm M
Oncogene 2018 07;37(27):3729-3739

ΔNp73 regulates the expression of the multidrug-resistance genes ABCB1 and ABCB5 in breast cancer and melanoma cells - a short report.
Sakil H, Stantic M, Wolfsberger J, Brage S, Hansson J, Wilhelm M
Cell Oncol (Dordr) 2017 Dec;40(6):631-638

TAp73 suppresses tumor angiogenesis through repression of proangiogenic cytokines and HIF-1α activity.
Stantic M, Sakil H, Zirath H, Fang T, Sanz G, Fernandez-Woodbridge A, et al
Proc. Natl. Acad. Sci. U.S.A. 2015 Jan;112(1):220-5

JNK-NQO1 axis drives TAp73-mediated tumor suppression upon oxidative and proteasomal stress.
Kostecka A, Sznarkowska A, Meller K, Acedo P, Shi Y, Mohammad Sakil H, et al
Cell Death Dis 2014 Oct;5():e1484

MYC proteins promote neuronal differentiation by controlling the mode of progenitor cell division.
Zinin N, Adameyko I, Wilhelm M, Fritz N, Uhlén P, Ernfors P, et al
EMBO Rep. 2014 Apr;15(4):383-91

TAp73 is required for macrophage-mediated innate immunity and the resolution of inflammatory responses.
Tomasini R, Secq V, Pouyet L, Thakur A, Wilhelm M, Nigri J, et al
Cell Death Differ. 2013 Feb;20(2):293-301

X-ray phase-contrast CO(2) angiography for sub-10 μm vessel imaging.
Lundström U, Larsson D, Burvall A, Scott L, Westermark U, Wilhelm M, et al
Phys Med Biol 2012 Nov;57(22):7431-41

The MYCN oncogene and differentiation in neuroblastoma.
Westermark U, Wilhelm M, Frenzel A, Henriksson M
Semin. Cancer Biol. 2011 Oct;21(4):256-66

PRIMA-1(MET)/APR-246 targets mutant forms of p53 family members p63 and p73.
Rökaeus N, Shen J, Eckhardt I, Bykov V, Wiman K, Wilhelm M
Oncogene 2010 Dec;29(49):6442-51

Regulation of tumor suppressor p53 at the RNA level.
Vilborg A, Wilhelm M, Wiman K
J. Mol. Med. 2010 Jul;88(7):645-52

Isoform-specific p73 knockout mice reveal a novel role for delta Np73 in the DNA damage response pathway.
Wilhelm M, Rufini A, Wetzel M, Tsuchihara K, Inoue S, Tomasini R, et al
Genes Dev. 2010 Mar;24(6):549-60

The p53 target Wig-1 regulates p53 mRNA stability through an AU-rich element.
Vilborg A, Glahder J, Wilhelm M, Bersani C, Corcoran M, Mahmoudi S, et al
Proc. Natl. Acad. Sci. U.S.A. 2009 Sep;106(37):15756-61

TAp73 regulates the spindle assembly checkpoint by modulating BubR1 activity.
Tomasini R, Tsuchihara K, Tsuda C, Lau S, Wilhelm M, Rufini A, et al
Proc. Natl. Acad. Sci. U.S.A. 2009 01;106(3):797-802

TAp73 knockout shows genomic instability with infertility and tumor suppressor functions.
Tomasini R, Tsuchihara K, Wilhelm M, Fujitani M, Rufini A, Cheung C, et al
Genes Dev. 2008 Oct;22(19):2677-91

Tumour Biology