When Cell Membrane “Hands” Feel Strain, They Pull Levers Loosing Cancer

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If you were to inspect a typical Rube Goldberg contraption, you wouldn’t be surprised to see mechanical hands. For example, such a contraption could impart motion to a backscratcher or something else just as innocent, at least on the human scale. On the molecular scale, however, such a contraption could trigger harmful actions. In fact, there is a cell membrane protein called syndecan-4 that can, as part of a mechanotransduction pathway, lead to cancer.

Syndecan-4’s potentially dangerous manipulations were recently uncovered by scientists based at Imperial College London. The protein combines with fellow cell membrane proteins, called integrins, to form protruding “hands” that sense the environment outside the cell. Both proteins are transmembrane receptors. When they form complexes together, syndecan-4 tunes cell mechanics in response to localized tension via a coordinated mechanochemical signaling response. Ultimately, this membrane-embedded mechanism can trigger some of the cellular processes behind cancer and other diseases.

The discovery of these not-so-idle hands could present a new research pathway and drug target for certain cancer types. “Our findings,” said Imperial’s Armando del Río Hernández, PhD, senior lecturer in the department of bioengineering, “could have immediate implications in the fields of cell and developmental biology, and lead to developments in several diseases including cancer and fibrosis.”

Details of the new work appeared January 6 in Nature Materials, in an article titled, “Syndecan-4 tunes cell mechanics by activating the kindlin-integrin-RhoA pathway.” The article describes how localized tension on syndecan-4 initiates an adaptive stiffening response through a mechanosignaling cascade that requires synergistic cell-wide activation of β1 integrins and the formation of new integrin–extracellular matrix connections, followed by subsequent RhoA-induced actomyosin contractility.

“Tension on syndecan-4 induces cell-wide activation of the kindlin-2/β1 integrin/RhoA axis in a PI3K-dependent manner,” the article’s authors indicated. “Furthermore, syndecan-4-mediated tension at the cell–extracellular matrix interface is required for yes-associated protein activation. Extracellular tension on syndecan-4 triggers a conformational change in the cytoplasmic domain, the variable region of which is indispensable for the mechanical adaptation to force, facilitating the assembly of a syndecan-4/α-actinin/F-actin molecular scaffold at the bead adhesion.”

Syndecan-4 exists in nearly every human cell and is already known for its role in cardiovascular disease. However, its potential roles in cancer biology and drug development have thus far been overlooked.

To study syndecan-4 the Imperial research team, led by del Río Hernández, used biophysical, cell biology, and computational techniques. The team found that activating the cellular “hands” triggers a pathway with key roles in disease development, involving a cellular protein called the yes-associated protein (YAP). Specifically, the team established that syndecan and integrin engage in force-dependent crosstalk, acting synergistically to induce RhoA activation, adaptive stiffening and YAP transcriptional signaling.

YAP triggers some of the typical hallmarks of cancer. It reduces cells’ ability to program their own death. That is, it inhibits apoptosis, a process that cells initiate when they age or malfunction. When apoptosis is halted, diseased and cancerous cells may spread. YAP also controls the development of blood vessels—a hallmark of cancer as tumor growth requires extra blood flow.

del Río Hernández and colleagues also found that syndecan-4 helps cells respond to movements outside themselves, by creating tension in the cytoskeleton—the “scaffolding” within cells. This makes cells stiffen, which activates an enzyme called PI3K that regulates additional hallmarks of cancer.

It does this by converting the movements outside the cell into biochemical signals which, the researchers found, “tune” the way the cells respond to tension and movement.

“The way cells interact with their environment could inform how we engineer tissues and mimic human organs for drug design,” noted del Río Hernández. “Syndecan-4 could now play a fundamental part in this endeavor.”

Co-lead author Stephen Thorpe, PhD, researcher co-investigator at Queen Mary University of London said: “As syndecan-4 is expressed on almost all of our cells, the mechanisms we’ve uncovered could be targeted to alter any number of diseases and biological processes.”

The research team plans to investigate syndecan-4’s links to specific diseases such as pancreatic cancer. “Our next approach,” remarked del Río Hernandez, “will involve syndecan-4 as a key contributor in disease. We hope this will lead to new insights into disease mechanisms.”

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