Margareta Wilhelm Group
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.
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.
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.
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.
p53 controls genomic stability and temporal differentiation of human neural stem cells and affects neural organization in human brain organoids.
Marin Navarro A, Pronk RJ, van der Geest AT, Oliynyk G, Nordgren A, Arsenian-Henriksson M, et al
Cell Death Dis 2020 01;11(1):52
Modeling SHH-driven medulloblastoma with patient iPS cell-derived neural stem cells.
Susanto E, Marin Navarro A, Zhou L, Sundström A, van Bree N, Stantic M, et al
Proc. Natl. Acad. Sci. U.S.A. 2020 Aug;():
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 01;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 HAM, Wilhelm MT
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 HAM, Stantic M, Wolfsberger J, Brage SE, Hansson J, Wilhelm MT
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 HA, 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 HA, 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 AK, 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 DH, Burvall A, Scott L, Westermark UK, Wilhelm M, et al
Phys Med Biol 2012 Nov;57(22):7431-41
The MYCN oncogene and differentiation in neuroblastoma.
Westermark UK, Wilhelm M, Frenzel A, Henriksson MA
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 VJ, Wiman KG, Wilhelm MT
Oncogene 2010 Dec;29(49):6442-51
Regulation of tumor suppressor p53 at the RNA level.
Vilborg A, Wilhelm MT, Wiman KG
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 MT, Rufini A, Wetzel MK, 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 JA, Wilhelm MT, 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 SK, 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 CC, et al
Genes Dev. 2008 Oct;22(19):2677-91