Decoding the role of Netrin-1 receptor shedding during cancer cell survival

• Applicant: Denise Nikodemus, Ph.D.
• Subject Area: Cell Biology ; Biochemistry
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 409684139

Cancer is a leading cause of death worldwide and its incidence is rising. Therefore, in order to invent effective therapeutics, it is of global and urgent interest to understand the molecular mechanisms of cancer development and progression. Deregulation of programmed cell death, known as apoptosis, is a key strategy of cancer cells to ensure their own survival. However, how cancer cells escape cell death is poorly understood. Tumour surrounding stromal cells significantly influence tumour progression. Here, I identified the secreted extracellular matrix protein Netrin-1 to be highly up-regulated in stromal cells in response to invasive cancer cell stimuli. Netrin-1, a neuronal guidance molecule, has emerged as an essential cell survival factor in cancer, acting through its dependence receptors. In the absence of Netrin-1, these receptors induce apoptosis. Thus, targeting Netrin-1 receptor signalling represents a promising therapeutic approach. My preliminary data decode a novel mechanism through which cancer cells regulate Netrin-1 receptor induced cell fate. Here, ADAM metalloproteases ensure the equilibrium between cell survival and cell death by shedding netrin-1 receptors. Based on my data, I hypothesize that elimination of Netrin-1 together with blockade of Netrin-1 receptor shedding induces cancer cell apoptosis. To translate my findings into the clinic, I will develop blocking peptides and/or antibodies to inhibit tumour progression by causing cancer cell death. Thus, successful completion of this project will not only yield in-depth insight into a novel molecular mechanism of Netrin-1 receptor shedding through metalloproteases during cancer cell survival, but also identify a promising strategy for cancer therapy.

• DFG Programme: Research Fellowships
• International Connection: Denmark
• Host: Marie Kveiborg, Ph.D.