Newly discovered cell signalling platform could enable metastasis
Metastasis, or cancer spreading, is still one of the biggest challenges in cancer research and treatment. It is often not the original tumour that kills, but secondary growths; metastases. These happen when cells are able to break away from the primary site, travel around the body and “seed” new tumours.
We have many natural defences against cancer that must break down or be overcome before cancer can take hold. One of these is making sure cells are always attached (or "adhered") – both to one another and to their environment. Cells that detach are usually killed in a process called anoikis.
However, clearly, for cancer cells to spread around the body they must avoid this protective killing mechanism and learn to survive. Stéphanie said:
Metastasis is currently incurable and remains one of the key targets of cancer research. Our research advances the knowledge of how two key molecules communicate and work together to help cancer cells survive during metastasis.
We’re hoping that this might lead to the discovery of new drugs to block the spread of cancer within the body.
A new study from our Centre for Tumour Biology may have found one of the keys to this survival that permits metastasis.
For the millions – trillions – of cells in our body to know how to respond and behave in their respective organs, they must communicate with the environment. This typically goes in both directions; signals from outside the cell can tell it what to do, and the cell can affect the environment by signalling out.
One major way cells interact with their surroundings is via integrins. These are proteins on the cell surface that attach to proteins in the extracellular matrix; an organised mess of strands and particles that gives structure to tissues and provides attachment points for cells.
Both integrin “outside-in” and “inside-out” signalling have been studied in detail, but the group’s work reveals an entirely new form of communication – “inside-in” signalling, as they have named it, in which integrins talk from inside the cell to itself.
This internal chatter is very much out of character compared to what we’ve learned about integrins so far.
What’s going on?
Stephanie’s team has shown that an integrin called beta-1 (β1) pairs up with another cell surface signalling protein called c-Met. They then move inside the cell together, carried on a small ‘bubble’ of membrane that forms at the surface and moves inwards.
This bubble is of a particular type, similar to ones that form when cells recycle things they don’t need any more, making useful building blocks available again – a process called autophagy. These membranes have never been thought to play a role in cells’ communication until now.
We could almost think of it as if our recycling service suddenly started distributing the mail.
The authors have named this new type of internal membrane “autophagy-related endomembrane” or ARE. β1 integrin and Met signal together from this part of the cell to cause a chain reaction that allows cells to survive while “floating” – essential if a cancer cell is to break away from the tumour it came from.
They have shown using both breast and lung cells - in both mouse and zebrafish models - that metastases are less likely to form when β1 is prevented from interacting with Met, or they are blocked from entering the cell together.
Met and integrins are major targets for cancer treatment. Inhibitor drugs for both Met and some integrins have been developed and are being tested in the clinic – but the failure of integrin inhibitors could be partly explained by this newly discovered inside-cell function.
The discovery could contribute to a better understanding of how cells break away from tumours and metastasise – and to more effective treatment combinations that could both prevent and slow tumour growth and spread.
The research was funded by the UK Medical Research Council, Breast Cancer Now, Rosetrees Trust, British Lung Foundation, Cancer Research UK and Barts and The London Charity
Beta 1-integrin- c-Met cooperation reveals an inside-in survival signalling on Autophagy Related Endomembranes
Barrow-McGee R, Kishi N, Joffre C, Ménard L, Hervieu A, Bakhouche BA, Rivero AJN, Mai A, Gutierr CG, Robert-Masson L, Iturrioz X, Hulit J, Brennan C, Hart IR, Parker PJ, Ivaska J, Kermorgant S. Nature Communications (2016) DOI: 10.1038/NCOMMS11942
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