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Systems Biology of Cancer

Cancer is a disease in which complex changes in cellular regulatory and signaling processes lead to uncontrolled proliferation of cells. One of the central pathways regulating cell division and cell death is the EGFR pathway, it is hence no surprise that deregulation of EGF signaling is a hallmark of many cancers. Three main pathways downstream of EGFR are activated by EGFR: First, the RAS-RAF-MAPK pathway, which affect cell proliferation, tumor invasion, and metastasis. Second, the PI3K/AKT pathway, which activates the cellular survival pathways and anti-apoptotic signals such as NFKB. Third, the JAK/STAT pathway, a central pathway in the cellular innate immune response, which is also implicated in the activation of genes associated with cell survival.

Deregulation of EGFR Signaling in Cancer

Activation of EGF signaling by EGF receptor internalization is a first step in this signaling cascade. Recent experiments observe a change in the moed of EGFR internalization from clathrin mediated endocytosis (CME) to clathrin independent endocytosis (CIE) with rising EGF concentration. Due to different fates of receptors internalized via CME or CIE, this alters the receptor trafficking and modulates the associated signaling.

In this project, we have developed a novel mathematical model of EGFR trafficking, to describe the dose dependent regulation of the receptor localization and transport. Model predictions are in close agreement with experimental data, and provide valuable insights into the dose-dependent attenuation of EGF signal transduction.

EGFR Trafficking, HPV Infection and Cervical Cancer

In collaboration with our experimental partners at the German Cancer Research Center, we are currently studying how human papillomavirus (HPV) interferes with EGFR trafficking. Infection with HPV causes dereglation of EGFR trafficking and signal transduction, ultimately leading to cervical cancer. The exact mechanism and nature of the underlying changes is unknown; we will tackle this question using a combination of life cell imaging and mathematical modeling.