Unraveling the Secrets of Cancer – One Cell at a Time

Cancer occurs when normal, healthy homeostasis of a given tissue is lost and uncontrolled proliferation of malfunctioning tumor cells take over the organ. The development of cancer (i.e. tumorigenesis) is a multi-step process that starts with the acquisition of genetic mutations that lead to the transformation of normal cells into malignant cancer cells that fail to respond to microenvironmental control factors and multiply in an unregulated fashion. Over the past decades, we have learned a lot about the cancer-initiating genetic mutations within a cell that cause this transformation. In our work, we utilize microfluidics- and droplet-based single cell analysis tools to grasp the spectrum of cellular heterogeneity during normal homeostasis in order to understand how the system changes in single cell resolution during the first initial phases of tumorigenesis.

Our interdisciplinary research approach will identify biomarkers for early detection and may ultimately lead to the discovery of novel therapeutic approaches to treat or even prevent breast cancer before it develops.

“No cell is an island” – Understanding the communication between cells and their exterior

The cells of the body are embedded into a three dimensional cellular microenvironment consisting of extracellular matrix (ECM), neighboring cells and a plethora of soluble secreted factors such as growth factors, cytokines and chemokines. Every single cell uses multiple classes of receptors that enable it to sense its microenvironment and to change its biology quite drastically depending on the signals provided by the exterior.

We are interested in the cellular and molecular mechanisms of cell communication and the detailed composition of the microenvironment within the niche harboring breast epithelial stem cells. Our recent work has firstly described that matrix metalloproteinases are extrinsic regulators of mammary stem cell function that modulate cellular communication through the specific interaction with non-canonical Wnt ligands (Kessenbrock et al., Cell Stem Cell, 2013). We found that relatively subtle changes in this system can cause distortion of this communication leading to elevated stem cell proliferation and ultimately tumor formation.

Our ongoing projects are expanding on these findings and focus on the role of non-canonical Wnt signaling in the control of mammary stem cell biology and breast cancer. We are also using unbiased “bottom-up” approaches such as single cell RNA sequencing and mass spectrometry analyses of stem cell supporting niche cells to identify novel key players involved in mammary stem cell maintenance and breast cancer. We will use mouse models for breast cancer and use human breast cancer samples to understand how the microenvironment changes during tumorigenesis and metastasis.

Extracellular proteases as shapers of the tumor microenvironment

Tumors exploit the body’s own infrastructure in multiple ways. Ongoing projects explore the interplay between malignant tumor cells and inflammatory cells focusing on extracelllular proteases as microenvironmental regulators.

In ongoing work, we study a unique form of cell death of neutrophil granulocytes, called neutrophil extracellular trap (NET) formation, which is characterized by the active release of nuclear chromatin into the extracellular space. These DNA-rich NETs are decorated with copious amounts of proteases and other factors, which have potent effects on the local microenvironment. We have previously found that these NETs are involved in human autoimmune diseases such as small-vessel vasculitis (Kessenbrock et al., 2009, Nat. Med.). We are currently exploring whether NET formation plays a role in breast cancer progression and metastasis.