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Body and mind

Malfunctioning cellular antennae lead to cancer

Cancer may arise when cells in our body stop operating normally. In healthy cells, several regulatory mechanisms counteract potential malfunctions, and an imbalance in these mechanisms may therefore have severe consequences. Danish researchers have revealed a previously unknown mechanism by which cells ensure that they receive the right type and volume of signals from their surroundings. If this regulation breaks down, signalling runs riot, which can lead to cancer and other diseases. This new knowledge may improve the diagnosis and treatment of cancer patients.

Roof-mounted satellite antennae are precisely tuned in to pick up and transmit TV signals to the residents of homes around the world. If the antenna points in the wrong direction or if the wiring to the TV is defective, the signal may be severely compromised. Similarly, most cells in the human body are equipped with an antenna – a primary cilium – that helps to receive and translate surrounding signals into cellular responses that ensure proper fetal development and functioning of tissues and organs in adults. A research group from the University of Copenhagen recently published an article in Cell Biology describing how the antennae translate environmental cues.

“We know that defects in the cells’ antennae – the primary cilia – may result in severe fetal abnormalities and disease progression in adults. We were therefore very interested in better understanding how these antennae maintain their sensory capacity while ensuring that the signalling from the antennae to the cells are correctly balanced to control cellular processes. Our research revealed a novel mechanism that helps to regulate this, and we discovered that a malfunction in this mechanism leads to a very dangerous situation in which cell signalling runs riot,” explains Søren Tvorup Christensen, Professor, Department of Biology, University of Copenhagen.

A key component in communication

The cells ensure that they receive the right signals by using cancer-blocking proteins to ensure that the receptors in the antennae are correctly located and, when they are positioned in the antennae, these proteins ensure that the receptors are not overactivated. Cancer may arise if this inhibition system fails.

“In the long term, we hope that our discovery may help us to improve the diagnosis and treatment of people who have defects in this safeguard system.”

More specifically, the researchers examined platelet-derived growth factor receptor alpha (PDGFRα), which the researchers had previously discovered operates in the antennae of the cells and, when defective, plays a key role in many types of cancer, including the formation of tumours in the brain and in the gastrointestinal system. The key question therefore was how these antennae help to ensure that this receptor is not overactivated, which is associated with cancer-causing signalling in various types of cells.

“We discovered that a specific group of cancer-blocking proteins from the Cbl protein family help to ensure that PDGFRα is correctly transported to the antennae. When growth factors from the surroundings activate the receptors, the Cbl proteins in the antennae then start to downregulate the receptors in a way that ensures a fine balance in the signalling output from the receptors.”

Inhibiting the effects of the malfunction

Cbl proteins therefore play a key role in regulating the sensory function of the antennae and in ensuring that cells receive and transmit the correct quantity of signals. However, these cancer-blocking proteins must be stabilized for this to work. The researchers found that stabilization is regulated by another protein called IFT20, which is a key component in understanding the communication through the primary cilia.

“A reduction in the cellular production of IFT20 had dire consequences for the cells. Without IFT20, the Cbl proteins became unstable and underwent self-destruction, which in turn led to mislocalization of the receptors to the general cell surface from which the receptors were wildly overactivated. This type of overactivation is precisely what is seen in certain types of cells that form tumours in the brain and gastrointestinal system. IFT20 thus plays a vital role in maintaining normal signalling in healthy cells.”

This new discovery may prove to be a major breakthrough in the treatment of people with cancer as well as in other diseases in which Cbl proteins are working properly, such as in autoimmune diseases. Although the researchers’ new discovery will not lead directly to any new treatment, the perspectives may be far-reaching in improving the diagnosis and treatment of people with cancer and other severe illnesses.

“We hope that our findings can be used in the future as a novel diagnostic tool for identifying individuals who have increased risk of certain types of cancer, similarly to what doctors are doing today in screening patients for specific mutations in cancer genes such as inherited mutations in BRCA genes, which increase the risk of female breast and ovarian cancer. Further, our results could lead to the development of drugs that target the type of overactivation of receptor signalling we saw in our study,” concludes Søren Tvorup Christensen.

IFT20 modulates ciliary PDGFRα signaling by regulating the stability of Cbl E3 ubiquitin ligases” has been published in Cell Biology. The research is the result of 5 years of intensive basic research supported by funding from Independent Research Fund Denmark, the Lundbeck Foundation, the Novo Nordisk Foundation, the Danish Cancer Society, the Carlsberg Foundation, the Swiss Velux Foundation and funding from the University of Copenhagen’s Excellence Programme for Interdisciplinary Research.

Søren Tvorup Christensen
Professor
Primary cilia are surface-exposed sensory organelles that regulate a vast number of cellular signaling pathways to control the development and function of multiple tissues and organs. Ciliary defects therefore result in numerous diseases and pleiotropic syndromes called ciliopathies. We employ a variety of different approaches, from biochemistry, molecular biology and proteomics to mammalian cell cultures and zebrafish models, to study the molecular mechanisms by which cilia assemble, disassemble, and function to coordinate cellular signaling networks during development and tissue homeostasis. These studies include the mechanisms by which the balanced activation of ciliary signaling is regulated by microtubule-dependent vesicular trafficking to and from cilia, and how defects in these processes are linked to cancer and developmental disorders, including congenital heart and brain diseases. Recently, we uncovered a series of new pathways and molecules that modulate the ability of primary cilia to respond to specific growth factors and morphogens in Hedgehog, PDGFRα and TGFβ/BMP signaling and to adjust the signaling output of receptor activation. These results provide important molecular insight into the etiology of ciliopathies and identify new candidate disease genes.