“Will you just stand still?” Scientists gain insight into metastatic lung cancer

By Katarzyna Makowska
School of Molecular and Cellular Biology, University of Leeds, UK

This summary was highly commended by the judges for Access to Understanding 2013

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Brian J. McHugh and colleagues from University of Edinburgh and King’s College London have discovered a one-protein switch that makes normal lung cells behave like metastatic cancer cells. This exciting finding, published in PLOS One in July 2012, brings us closer to conquering lung cancer.

What are we up against?

Lung cancer is very common and has very high mortality rates. It kills more people than any other cancer in the Western World, including the UK. Small cell lung cancer (SCLC) is an extremely aggressive form of the disease that grows quickly and spreads rapidly to other parts of the body, creating new tumours called metastases. As one can imagine, multiple tumours spreading in the organism are very difficult to deal with, and as a result, only less than 1 in 7 small cell lung cancer patients show long-term survival. This is also why researchers are always seeking new ways to fight the lung cancer.

What makes cancer so dangerous?

Several things make cancer such a serious disease. Unlike normal cells, cancer cells can appear to be immortal, grow uncontrollably and divide almost without limits, but the biggest problem is that they can become more mobile and invasive than healthy cells. Normal cells do not usually move, but cancer cells ‘conquering’ other tissues can cause a lot of damage. The migration of cells depends on many factors, such as the cytoskeleton (scaffolding inside the cell), neighbouring cells or the external environment, generally called the extracellular matrix (ECM). In many cases, although not always, attachment to ECM is necessary to sustain the migrating cells. Several groups of proteins are extremely important for this process, including integrins.

What are integrins?

Integrins are crucial proteins in cell migration, because they are integrated into the cell membrane and are responsible for cells attaching to surfaces, a kind of molecular ‘glue’. Their important role is to integrate, thus the name, the inside of the cell (cytoskeleton) to the outside (ECM and other cells). Integrins get cues about the environment and distribute the information in the cell, so that the cell knows how to behave and can respond accordingly. It is not surprising then that the levels and activities of integrins change in many types of cancer, and help to promote cell migration or metastasis.

How can normal cells mimic metastatic cancer?

Integrins can be influenced by other proteins. In this new study, the researchers focused on Fam38A, which helps to switch on the integrins. They showed that Fam38A is found at high levels in normal lung cells but it is almost absent in small cell lung cancer cells. To discover if this is important in driving lung cancer metastasis, they ‘silenced’ the expression of this protein in normal cells, so that its level was similar to that in cancerous cells. They found that when Fam38A is almost missing, integrins become inactive, and the cells stop adhering to their surroundings as readily as normal cells. Surprisingly, the cells missing Fam38A were also shown to eagerly move around and to be more invasive than normal lung cells.

The next question to ask is how is this possible? How can the cells migrate, when levels of active integrins are low, and cells need integrins to adhere at least in some types of migration? The exciting answer is that their movement no longer depends on integrins. The cells can switch to so-called amoeboid migration, when they move similarly to free-living single celled organisms called amoeba. Amoeboid migration is known to be often used by various cancer types, including small cell lung cancer.

What does this mean for the patients?

This intriguing discovery shows that the loss of one humble protein causes a fundamental change in cell behaviour. If it has such drastic consequences for cell migration, Fam38A is likely to be very important for lung cancer metastasis. For example, detecting low levels of Fam38A in tumours during screening is likely to mean that the cancer has higher potential to become aggressive and metastatic.

Further studies seem necessary before this finding can be applied clinically. Nevertheless, it certainly helps to unveil the mechanisms behind cancer metastasis and hopefully will contribute to discovering new therapies for lung cancer in the future.

This article describes the research published in:

Loss of the integrin-activating transmembrane protein Fam38A (Piezo1) promotes a switch to a reduced integrin-dependent mode of cell migration (2012) B. J. McHugh, A. Murdoch, C.Haslett, T. Sethi PLoS One 7(7), e40346
http://EuropePMC.org/articles/PMC3390408

This article was selected for inclusion in the competition by Chief Scientist Office of the Scottish Government.