Cohen/Herranz Group – University of Copenhagen

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Department of Cellular and Molecular Medicine > Research groups > Cohen/Herranz Group

Cohen/Herranz Group

Morphogenesis and Differentiation Program

Research Interests

microRNA functions in development and disease, using Drosophila.

Background
Cancer develops in a complex mutational landscape. Cancer cells accumulate ‘driver mutations’ that are causally linked to disease, and ‘passenger mutations’ that, although present, have limited impact on disease. In recent years, factors encoded by cancer genes have become targets for successful anticancer drug development. Although cancer genome sequence data provide an unparalleled depth of information about the mutations present in different cancer genomes, identification of genetic alterations contributing to tumorigenesis and metastasis calls for the use of simple genetic model systems.

Tumors exhibit another dimension of complexity: the tumor microenvironment. Carcinomas are composed by different cell types: the neoplastic epithelial compartment, and the tumor stroma that comprises associated mesenchymal cells and Extracellular matrix. Interaction of cancer cells with the tumor stroma can modify the local microenvironment to promote disease progression.  Therefore, understanding how tumor cells interact with the stromal environment will be important for understanding disease progression.

Current Project Areas

We are using Drosophila melanogaster as a tumor model system.
We have engineered Drosophila strains that activate different cancer-driver mutations. These flies allow, with a single genetic cross, the introduction of new mutations to identify genes that, when combined with driver mutations, lead to tumor formation and metastasis.

Top - Oncogenic cooperation between the oncogene EGFR and the gene psq.

Bottom - GFP-labeled metastasis infiltrating other organs as the malpighian tubules or the gut.

We have developed a Drosophila model to dissect the crosstalk between tumor cells and surrounding normal cells, in tumors of epithelial origin. In this model, interaction between the two cell populations is required for tumor growth, neoplastic transformation of the epithelium, and metastasis. Our aim is to understand the molecular crosstalk between these cell populations driving tumor and metastasis formation.

Top - Drosophila tumors of epithelial origin composed by a mix of epithelial transformed cells (GFP+), and wild type mesenchymal cells (GFP-) corresponding to the tumor stroma.

Bottom - Epithelial mutant compartment (GFP+) expresses TGF-β (dpp), whereas the tumor stroma (GFP-) activates TGF-β pathway (pMAD).

Selected publications

Chen Y-W, Song, S., Weng, R., Verma, P., Kugler, J.-M., Buescher, M., Rouam, S., & Cohen, S.M. (2014). Systematic study of Drosophila microRNA functions using a collection of targeted knockout mutations. Dev Cell, in press DOI: 10.1016/j.devcel.2014.11.029

Foronda, D., Weng, R., Verma, P., Chen. Y.-W. & Cohen S.M. (2014) Coordination of Insulin and Notch pathway activities by microRNA miR-305 mediates adaptive homeostasis in the intestinal stem cells of the Drosophila gut. Genes Dev 28: 2421-2431. DOI: 10.1101/gad.241588.114

Hong, X., Nguyen H.T., Chen Q., Zhang, R., Hagman, Z., Voorhoeve, P.M. & Cohen, S.M. (2014). Opposing activities of the Ras and Hippo pathways converge on regulation of YAP protein turnover. EMBO J DOI: 10.15252/embj.201489385  

Nguyen H.T., Hong, X., Tan, S., Chen Q., Chan,L., Fivaz.M., Cohen, S.M. & Voorhoeve, P.M. (2014) Viral small T oncoproteins transform cells by alleviating Hippo pathway-mediated inhibition of the YAP proto-oncogene. Cell Reports 8, 707-713. doi: 10.1016/j.celrep.2014.06.062

Herranz H*, Weng R and Cohen SM*. Crosstalk between Epithelial and Mesenchymal Tissues in Tumorigenesis and Imaginal Disc. Current Biology, 24, 1–9, July 7, 2014 *Corresponding author Access the recommendation on F1000Prime 

Zhang, W., Hietakangas,V., Wee, S.,  Lim, R.  Gunaratne, J., and Cohen, S.M.  (2013) ER stress potentiates insulin resistance through PERK-mediated FOXO phosphorylation. Genes Dev 27(4):441-9

Herranz H*, Hong X*, Hung NT, Voorhoeve PM and Cohen SM. Oncogenic cooperation between SOCS family proteins and EGFR identified using a Drosophila epithelial transformation model. Genes Dev, 2012 Jul 15; 26: 1602-1611 *These authors contributed equally to this work.

Herranz H, Hong X and Cohen SM. Mutual Repression by Bantam miRNA and Capicua Links the EGFR/MAPK and Hippo Pathways in Growth Control. Current Biology, 22, 1–7, April 24, 2012

Herranz H and Cohen SM. MicroRNAs and gene regulatory networks: managing the impact of noise in biological systems. Genes Dev, 2010 Jul 1;24(13):1339-44

Herranz H, Hong X, Pérez L, Ferreira A, Olivieri D, Cohen SM and Milán M. The miRNA machinery targets Mei-P26 and regulates Myc protein levels in the Drosophila wing. EMBO J, 2010 May 19;29(10)

Varghese, J., Lim, S., and SM Cohen (2010) Drosophila miR-14 regulates insulin production and metabolism through its target sugarbabe. Genes Dev. 24: 2748-2753.

Herranz, H. and SM Cohen (2010) microRNAs and gene regulatory networks: managing the impact of noise in biological systems. Genes Dev 24, 1339-1344

Hong, X., Hammell, M. Ambros, V and Cohen, S.M. (2009) Identification of microRNA targets by immunopurification of Ago1 RNPs: selection for a distinct class of targets. PNAS 106, 15085-90.

Bushati, N., Stark, A., Brennecke, J., and Cohen, S.M. (2008) Temporal reciprocity of microRNAs and their targets during the maternal to zygotic transition in Drosophila. Current Biology 18, 501-506.

J Karres, V Hilgers, I Carrera, J Treisman & SM Cohen (2007) The conserved microRNA miR-8 tunes Atrophin levels to prevent neurodegeneration in Drosophila. Cell 131, 136–145.

BJ Thompson & SM Cohen  (2006) The Hippo pathway regulates the bantam microRNA to control cell proliferation and apoptosis in Drosophila. Cell.126, 767-774.

Stark, A., Brennecke, J., Bushati, N. Russell, R.B. & Cohen, S.M. (2005) Animal microRNAs confer robustness to gene expression and have a significant impact on 3’UTR evolution. Cell 123,1133-1146.

Brennecke, J., Hipfner, D.R. Stark, A., Russell, R & Cohen, S.M. (2003) bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the pro-apoptotic gene hid in Drosophila. Cell 113: 25-36.