Current research - Stenmark group

Cells in the body communicate by way of chemical signals (for instance, hormones or growth factors), which are sent by some cells and recognized by specific receptors on recipient cells. Binding of a chemical signal to its receptor may elicit a variety of different responses in the recipient cell, such as instructions to divide, migrate, undergo programmed cell death, or differentiate into a different cell type. In cancer, communication between cells is often faulty, which is one of the reasons why cancer cells divide and grow in an uncontrolled manner.

Cell surface receptors are key elements in cellular communication. When exposed perpetuously to a chemical signal, receptors at the cell surface usually decrease in numbers in order to avoid overstimulation of the recipient cell. When such downregulation is impaired, the recipient cell may, for instance, start dividing out of control. Indeed, defects in growth factor receptor downregulation have been discovered in several cancers.

Cell surface receptors can be downregulated by several mechanisms. One of the most important ones involves the internalization of the receptor by a process known as endocytosis, which means that the receptor is captured into a vesicle that pinches off inwards from the plasma membrane of the cell. The endocytic vesicle then fuses with an endosome, from which the receptor can be further transported to a degradative organelle, the lysosome. (See illustration).

Another pathway leading to  lysosomal degradation, autophagy, is also of interest in cancer research. This process involves the encapsulation of portions of cytoplasm by a double-membraned autophagosome, which can fuse with endosomes and lysosomes. Recent evidence suggests that autophagy functions tumour suppressive by degrading damaged organelles that would otherwise have given rise to genomic instability.

Recently our group has also become interested in cytokinesis, the final step of cell division, as it turns out that several components of the endocytic machinery controls this membrane involution pathway as well. Defective cytokinesis is associated with aneuploidy and is thought to play a role in carcinogenesis, and it is therefore important to elucidate how this process is regulated.

In our research group, we are trying to address the following questions:

• By which molecular mechanisms are endocytosed receptors transported to lysosomes?
• How important is endocytic receptor downregulation for the communication between cells?
• How do growth factors modulate endocytic downregulation and other intracellular trafficking pathways?
• How is cell communication coordinated with autophagy (lysosomal degradation of cytoplasm)?
• How does the endocytic machinery contribute to cytokinesis?

For these purposes, we make extensive use of cancer cell lines that are grown in tissue culture dishes. Such cells can be manipulated in many ways by various molecular biological methods and studied by advanced microscopy techniques or biochemical assays. As a complement to our tissue culture models, we have recently started to use a genetically modifiable model organism, the fruitfly Drosophila melanogaster, to study certain aspects of intracellular trafficking. In particular, this organism provides us with the opportunity to study the relationship between cell communication and intracellular trafficking in the context of a living organism.

Current projects involve:

• Determining the functions of phosphoinositides in cell signalling and carcinogenesis 
• Identifying regulatory mechanisms for cytokinesis, and their possible role in tumour suppression 
• Identifying regulatory and effector mechanisms for endocytic and autophagic membrane trafficking in Drosophila melanogaster and human cells.
• Understanding the molecular mechanisms of protein transport between endosomes and lysosomes
• Elucidating the role of phosphoinositide-binding proteins in autophagy