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Loss of Cell-Cell Adhesion and Tumour Progression

Focus: breast cancer

Breast cancer is the most common malignancy among females in the Western world resulting in approximately half a million deaths on an annual basis. In breast cancer, loss of E-cadherin is a decisive marker in the differential diagnosis of lobular and ductal carcinoma. While lobular carcinomas show loss of E-cadherin, most other breast carcinomas have retained expression. E-cadherin is a key component of adherens junctions, structures that play crucial roles in the maintenance of tissue integrity.

Dysfunction of epithelial adhesion complexes is strongly related to breast cancer invasion and metastasis. We are using mouse models of breast cancer in which inactivation of cell-cell adhesion through disruption of the adherens junction complex induces the formation of metastatic breast cancer. We are using several cell lines from our mouse models and human breast cancer to form a cell biological basis for understanding the malignant behavior of invasive cancer. We aim to identify the molecular cues that are triggered upon loss of cadherin-based cell-cell adhesions.

 For validation purposes, we have developed robust in vivo tumor progression and metastasis assays, based on orthotopic transplantation and bioluminescence imaging of luciferase-expressing cell lines, tumors and primary conditional and wild-type mouse mammary epithelial cells. We are using these assays to validate genes that are nominated as novel regulators of tumor initiation and progression.  To translate our findings, we are preforming preclinical interventions in mouse models of human metastatic breast cancer.

Key PUBMED Citations

Schackmann RCJ, Klarenbeek S, Vlug EJ, Stelloo S, van Amersfoort M, Tenhagen M, Braumuller TM, Vermeulen JF, van der Groep P, Peeters T, van der Wall E, Van Diest PJ, Jonkers J, Derksen PWB. Loss of p120-catenin induces metastatic progression of breast cancer by inducing anoikis resistance and augmenting growth factor receptor signaling. Cancer Res. 2013. 73(15):4937–49. PDF | PMID: 23733751
 
Schackmann RCJ, van Amersfoort M, Haarhuis JHI, Vlug EJ, Halim VA, Roodhart JML, Vermaat JS, Voest EE, van der Groep P, Van Diest PJ, Jonkers J, Derksen PWB. Cytosolic p120-catenin regulates growth of metastatic lobular carcinoma through Rock1-mediated anoikis resistance. J Clin Invest. 2011. 121(8):3176–88. PDF| PMID: 21747168
 
Derksen PWB, Liu X, Saridin F, Van Der Gulden H, Zevenhoven J, Evers B, van Beijnum JR, Griffioen AW, Vink J, Krimpenfort P, Peterse JL, Cardiff RD, Berns A, Jonkers J. Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell. 2006. 10(5):437–49. PMID: 17097565
 

People

  • Patrick Derksen
  • Miranda van Amersfoort
  • Robert van de Ven
  • Milou Tenhagen
  • Jolien de Groot
  • Eva Vlug

Undergraduates

  • Maria Boumpoutsari
  • Sander Boogaard

About the people

Jobs/Interships

All positions are filled. We are however always looking for good BSc or MSc/MD undergraduates who want to do their internship in our lab. To find out which projects can host an undergraduate internship, look at the projects page or call/e-mail us.

At the moment we are specifically looking for a SUMMA/MD undergraduate for a preclinical intervention study in mice. We are aiming at evolving this project into a PhD position. Please have a look here for a project description.

Contact

Department of Pathology | Heidelberglaan 100 | 3584CX Utrecht  | The Netherlands | Tel: +31 88 7568068
LAB: Stratenum 2.133 | Universiteitsweg 100 | 3584CG Utrecht | The Netherlands | Tel: +31 88 7556943

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