Cancer signaling

To properly respond to growth-stimulatory and growth-inhibitory signals in their micro-environment, cells possess multiple signal transduction pathways, consisting of specific enzymes, messenger and adaptor molecules that transmit these signals from their receptors to the nucleus, where transcription factors convert them into specific gene expression programs. To be able to integrate the information from different types and doses of stimuli that can reach a cell simultaneously or within short (repeated) intervals, signaling molecules from distinct pathways interact at many levels, both on the membrane, in the cytoplasm and in the nucleus, thereby forming large molecular networks that are often localized to specific sub-cellular structures. During carcinogenesis and cancer progression cells lose their ability to correctly respond to growth inhibitory signals, and/or show increased sensitivity to growth-stimulatory and pro-invasive signals. This is the result of genetic defects, such as mutation, deletion or amplification of specific signaling molecules, or due to epigenetic events such as gene silencing.

We are interested in the detection, identification and functional characterization of signaling complexes and intermediates that distinguish cancer cells from normal cells, or that differ during the different stages of tumor progression. These complexes might function as diagnostic and/or prognostic markers and become targets for (patient-specific) therapeutic intervention.

Current research

In close collaboration with the group of Peter ten Dijke we focus on components of the TGF-ß-Smad and MAP kinase-AP-1 pathways, which play critical roles in tumor progression and the cellular response to anti-cancer drugs and radiation, including therapy-resistance. These pathways interact at multiple levels (see figure below). TGF-ß-Smad signaling components play dual roles in cancer, as they can inhibit cell cycle progression and cell survival during early carcinogenesis but often enhance tumor cell migration, invasion and metastasis during the later stages. MAP kinases (ERK, JNK and p38) and their AP-1 transcription factor targets can also regulate cancer cell mobility and invasion. Moreover, MAP kinases and AP-1 transcription factors can either inhibit or stimulate cell proliferation and survival, dependent on cell type, cell stimuli, the oncogenic changes and the cellular environment. We use amongst others in situ proximity ligation assays (PLA) to study the involvement of the various AP-1 and Smad complexes in TGFß/Smad‑induced cell invasion. In addition, we use transcriptome and ChIP‑sequencing approaches to identify critical TGFb-regulated complexes and target genes that regulate tumor-cell properties such as epithelial-mesenchymal transition, invasion and drug-responses. The research is performed both in department of Molecular Cell Biology at the LUMC and in the Ludwig Institute for Cancer Research in Uppsala, Sweden (www.ludwigcancerresearch.org/location/uppsala-branch).

 

Schematic representation of the interplay between TGF-ß and growth-factor signaling

Inleiding image 




Transforming growth factor‑ß (TGF-ß) family ligands and growth factors (GF) activate their receptors at the cell membrane. TGF-ß receptors subsequently phosphorylate and activate R‑Smads, which form a complex with a co‑Smad and then translocate to the nucleus. GF receptors activate amongst others Ras proteins and MAP‑kinase cascades, which can activate AP‑1 transcription factors (Jun/Fos and Jun/ATF complexes). TGF-ß receptors can also activate MAPKs and AP‑1. In the nucleus, the Smad and AP‑1 complexes can interact and bind to DNA to activate various classes of genes implicated in cancer, e.g. extra-cellular matrix enzymes involved in tumor invasion. Some of the target genes encode (related)  growth factors, cytokines, signaling enzymes or transcription factors, which allow fine-tuning and mediate secondary responses, including negative and positive feed-back for transient and sustained signaling (red and blue dashed lines). NB Besides Smad‑ and MAPK‑mediated signaling, TGFß family members also can activate various other non‑Smad pathways (not shown) and transcription factors (X,Y) that can influence the activity of cancer-associated genes.

 

People

dr. Anders Sundqvist       senior postdoctoral fellow
LICR, Uppsala, Sweden  e-mail:    anders.sundqvist@licr.uu.se
  phone:    +46 18 16 04 08
  fax:       +46 18 16 04 20
  
dr. Oleks Voytyuk  Postdoctoral fellow
LICR, Uppsala, Sweden  
  
prof. dr. Peter ten Dijke       head of section
  
dr. ir. J.A.F. (Hans) van Dam       associate professor
 Recent publications
  • Wang S, Xie F, Chu F, Zhang Z, Yang B, Dai T, Gao L, Wang L, Ling L, Jia J, van Dam H, Jin J, Zhang L, Zhou F.YAP antagonizes innate antiviral immunity and is targeted for lysosomal degradation through IKKɛ-mediated phosphorylation.Nat Immunol. 2017 Jul;18(7):733-743. doi: 10.1038/ni.3744. Epub 2017 May 8.
  • Xie F, Jin K, Shao L, Fan Y, Tu Y, Li Y, Yang B, van Dam H, Ten Dijke P, Weng H, Dooley S, Wang S, Jia J, Jin J, Zhou F, Zhang L. FAF1 phosphorylation by AKT accumulates TGF-β type II receptor and drives breast cancer metastasis.Nat Commun. 2017 Apr 26;8:15021. doi: 10.1038/ncomms15021.
  • Jin K, Li T, van Dam H, Zhou F, Zhang L. (2017) Molecular insights into tumour metastasis: tracing the dominant events. J Pathol.241(5):567-577. doi: 10.1002/path.4871.
  • Zhou F, Li F, Fang P, Dai T, Yang B, van Dam H, Jia J, Zheng M, Zhang L. (2016) Ubiquitin-Specific Protease 4 Antagonizes Osteoblast Differentiation Through Dishevelled.J Bone Miner Res. 31(10):1888-1898. doi: 10.1002/jbmr.2863
  • Li Y, Jin K, van Pelt GW, van Dam H, Yu X, Mesker WE, Ten Dijke P, Zhou F, Zhang L. (2016) c-Myb Enhances Breast Cancer Invasion and Metastasis through the Wnt/β-Catenin/Axin2 Pathway. Cancer Res.76(11):3364-75. doi: 10.1158/0008-5472.CAN-15-2302
  • Liu S, de Boeck M, van Dam H, Ten Dijke P. (2016)Regulation of the TGF-β pathway by deubiquitinases in cancer.Int J Biochem Cell Biol. 76:135-45. doi: 10.1016/j.biocel.2016.05.001.
  • Carthy JM, Sundqvist A, Heldin A, van Dam H, Kletsas D, Heldin CH, Moustakas A. (2015)  Tamoxifen Inhibits TGF-β-Mediated Activation of Myofibroblasts by Blocking Non-Smad Signaling through ERK1/2. J Cell Physiol. Jun 10. doi: 10.1002/jcp.25049. [Epub ahead of print]
  • Li Y, Drabsch Y, Pujuguet P, Ren J, van Laar T, Zhang L, van Dam H, Clement-Lacroix P, and ten Dijke P. (2015)  Genetic depletion and pharmacological targeting of alphav integrin in breast cancer cells impairs metastasis in zebrafish and mouse xenograft models. Breast Cancer Res., Feb 25;17:28. doi: 0.1186/s13058-015-0537-8.
  • ten Dijke P,  and van Dam H. (2015)  14-3-3ζ Turns TGF-β to the Dark Side. Cancer Cell  27 ( 2), Febr 9, 151–153
  • Xie F, Zhang Z, van Dam H, Zhang L, Zhou F. (2014)  Regulation of TGF-β Superfamily Signaling by SMAD Mono-Ubiquitination.  Cells  3(4):981-993.
  • Zhang J, Zhang X, Xie F, Zhang Z, van Dam H, Zhang L, Zhou F. (2014)  The regulation of TGF-β/SMAD signaling by protein deubiquitination.  Protein Cell. 5(7):503-517. 
  • Zhang X, Zhang J, Zhang L, van Dam H, ten Dijke P. (2013). UBE2O negatively regulates TRAF6-mediated NF-κß activation by inhibiting TRAF6 polyubiquitination, Cell Res. Mar;23(3):366-77.  Epub 2013 Feb 5
  • Sundqvist A, Zieba A, Vasilaki E, Herrera Hidalgo C, Söderberg O, Koinuma D, Miyazono K, Heldin CH, Landegren U, ten Dijke Pand van Dam H. (2013) Specific interactions between Smad proteins and AP-1 components determine TGFb-induced breast cancer cell invasion   Oncogene Aug 1;32(31):3606-15. Epub 2012 Aug 27
  • Zhang L, Zhou F, Li Y, Drabsch Y, Zhang J, van Dam H, and ten Dijke P. (2012) Fas-associated factor 1 is a scaffold protein that promotes β-TRCP mediated β-catenin ubiquitination and degradation. J Biol. Chem. Aug 31;287(36):30701-10. Epub 2012 Jun 2
  • Zhang L, Huang H, Zhou F, Schimmel J, Pardo CG, Zhang T,Barakat TS,  Sheppard KA,Mickanin C, Porter JA,Vertegaal A, van Dam H,Gribnau J,  Lu C, and ten Dijke P. (2012) RNF12 controls embryonic stem cell fate and morphogenesis in zebrafish embryos by targeting Smad7 for degradation. Mol Cell, Jun 8;46(5):650-61. Epub 2012 May 3.
  • Sundqvist A, ten Dijke P, and van Dam H. (2012) Key signaling nodes in mammary gland development and cancer: Smad signal integration in epithelial cell plasticity. Breast Cancer Res.14:204 (8 February 2012). 
  • Zhou F, Zhang X,van Dam H, ten Dijke P, Huang H, Zhang L. (2012) Ubiquitin-specific protease 4 mitigates Toll-like/interleukin-1 receptor signaling and regulates innate immune activation. J Biol Chem. Mar 30;287(14):11002-10. Epub 2012 Jan 19.
  • Naber HPN, Wiercinska E, Pardali E, van Laar T, Nirmala E, Sundqvist A,van Dam H, van der Horst G, van der Pluijm G, Heckmann B, Danen E, and ten Dijke P. (2012) BMP-7 inhibits TGF-b-induced invasion of breast cancer cells through inhibition of integrin b3 expression. Cell Oncol Feb;35(1):19-28. Epub 2011 Sep 21.
  • Zhou F, Zhang L, van Laar T, van Dam H, and ten Dijke P. (2011) GSK3β inactivation induces apoptosis of leukemia cells by repressing the function of c-Myb.  Mol Biol Cell. Sep;22(18):3533-40.
  • Zhang L, Zhou F, van Laar T, Zhang J, van Dam H, ten Dijke P (2011) Fas-associated factor 1 antagonizes Wnt signaling by promoting ß-catenin degradation. Mol Biol Cell. 22(9):1617-24.
  • Wiercinska E,  Naber HPH, Pardali E, van der Pluijm G, van Dam H, ten Dijke P. (2011) The TGF-b/Smad pathway induces breast cancer cell invasion through the up-regulation of matrix metalloproteinase 2 and 9 in a spheroid invasion model system. Breast Cancer Res. Treat. Aug;128(3):657-66. Epub 2010 Sep 5.
  • Roukens MG,  Alloul-Ramdhani M, Baan B, Kobayashi K ,Peterson-Maduro J, van Dam H, Schulte-Merker S, Baker DA (2010) Control of Endothelial Sprouting by a Tel:CtBP Complex  Nature Cell Biology Oct;12(10):933-42.
  • Matic I, Schimmel J, Hendriks IA, van Santen MA, van de Rijke F, van Dam H, Gnad F, Mann M, Vertegaal AC (2010)  Site-Specific Identification of SUMO-2 Targets in  Cells Reveals an Inverted SUMOylation Motif  and a Hydrophobic Cluster SUMOylation Motif. Mol. Cell Aug 27;39(4):641-652.
  • Baan B, PardaliE, ten Dijke P, van Dam H (2010) In situ proximity ligation detection of cJun/AP-1 dimers reveals increased levels of cJun/Fra1 complexes in aggressive breast cancer cell lines in vitro and in vivo. Mol Cell Proteomics.  Sep;9(9):1982-90. Epub 2010 May 28.
  • Ramos Y, Hestand M, Verlaan M, Krabbendam E, Ariyurek Y, van Galen M, van Dam H, van Ommen G-J, den Dunnen J, Zantema A, ‘t Hoen P-B (2010) Genome-wide assessment of differential roles for p300 and CBP in transcription regulation. Nucleic Acids Res. Sep;38(16):5396-408.