Researchers reveal a potential cancer repressor function in a key protein

In a paper published in Nature Cell Biology, IBEC junior group leader Pere Roca Cusachs and his collaborators at Columbia University and Singapore’s Mechanobiology Institute reveal the potential of a protein found in cell cytoskeletons as a repressor of cancer.

The ability of cells to sense the rigidity of the extracellular matrix – a collection of molecules that provides structural and biochemical support – affects the regulation of their activity in development, wound healing and other essential processes.

Correspondingly, abnormal rigidity sensing by cells is involved in many medical disorders; for example, the anchorage-independent growth of cancer cells indicates that their rigidity sensing machinery is malfunctioning.

After forming adhesions to the matrix, cells test its rigidity by applying forces to it; these forces are applied via local micrometre-scale contractions, like steps, but how the force of these contractions is regulated by rigidity is unknown. We do know that on soft matrices, cells produce low forces, leaving the adhesions small, so the signals that promote cell growth and proliferation are absent; on stiffer substrates, stronger adhesions are built, thereby allowing them to exert higher forces and proliferate. Cancer cells, however, can override the requirement for stable adhesions in order to proliferate, so they are able to grow on soft matrices too.

The researchers analyzed rigidity sensing with a new high-resolution technology by tracking the cells’ displacement of flexible sub-micron pillars by contractile forces. They found that actomyosin-based contractile units (CUs) – which are like muscle fibres, but on a cellular level –simultaneously moved opposing pillars in regular-sized small steps, independent of rigidity. What correlated with rigidity was the number of steps taken to reach a force level that activated recruitment of α-actinin (an actin-binding protein with multiple roles in different cell types) to the CUs.

“When we removed a protein, tropomyosin 2.1, that normally restricts actomyosin, we observed much larger steps and higher forces – like those found in stiffer substrates – that resulted in a malfunction in rigidity sensing,” says Pere. “As a result, we can conclude that tropomyosin 2.1 acts as a suppressor of cell growth on soft matrices by cells usually able to do so, such as cancer cells, by controlling force production and supporting proper rigidity sensing.”

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Article: Haguy Wolfenson, Giovanni Meacci, Shuaimin Liu, Matthew R. Stachowiak, Thomas Iskratsch, Saba Ghassemi, Pere Roca-Cusachs, Ben O’Shaughnessy, James Hone & Michael P. Sheetz* (2015). “Tropomyosin Controls Sarcomere-like Contractions for Rigidity Sensing and Suppressing Growth on Soft Matrices”. Nature Cell Biology, epub ahead of print