Cancer is a disease that affects millions of people worldwide. It is characterized by the uncontrolled growth of abnormal cells that can invade surrounding tissues and spread to other parts of the body.
Freiburg researchers demonstrate that the transport of molecules along the cell’s skeleton plays a crucial role in cancer metastasis.
Metastasis occurs when cancer cells break free from a primary tumor and spread throughout the body, requiring them to sever connections with neighboring cells and migrate to other tissues. Signaling molecules released by the cancer cells drive both processes and thereby increase the malignancy of tumors.
A team of researchers led by Professor Robert Grosse and Dr. Carsten Schwan from the University of Freiburg discovered that the release of prometastatic factors, which drive the malignancy of tumors, is influenced by the cells’ skeleton. The findings were published in the journal Advanced Science.
Actin has several functions in cancer propagation
Actin filaments are part of the cell skeleton and essential for stability and motility. They form a network that dynamically builds up and gets broken down by the addition or detachment of building blocks at the filaments’ ends. These processes are precisely regulated by other molecules, such as so-called formins.
The dynamics of the actin-network enable the locomotion of cells, for example during development or wound closure, but also that of spreading cancer cells. Actin also plays a role in the transport of substances within the cell. However, this is less well understood than that of other intracellular transport mechanisms.
Super-resolution microscopy image of a cell. With fluorescent markers, the prometastatic factor ANGPTL4 is labeled in magenta, the molecule FMNL2 in green, and the actin cell skeleton in white. The blow-up shows a single vesicle containing ANGPTL4 at several consecutive time points. FMNL2 (green) induces the polymerization of actin filaments (white) at the vesicle, propelling it forward. The vesicle itself is only about 200 nanometers in diameter. Credit: Dennis Frank / University of Freiburg
The Freiburg researchers now found that the actin-network also enables the release of prometastatic factors. For their study, they used high-resolution microscopy to track the movement of individual transport vesicles within living cancer cells.
“We observed that ANGPTL4-loaded vesicles are conveyed to the periphery of the cell by means of dynamic and localized polymerization of actin filaments,” says Grosse, who is a member of the Cluster of Excellence CIBSS – Centre for Integrative Biological Signalling Studies at the University of Freiburg.
ANGPTL4 is an important prometastatic factor that promotes the formation of metastases in various types of cancer.
FMNL2 controls the transport of ANGPTL4 along actin filaments
Based on the microscopic observations and genetic analyses, the scientists conclude that the vesicles’ movement is controlled by the formin-like molecule FMNL2 by initiating polymerization – i.e. elongation – of actin filaments directly at the vesicle.
“We already knew that increased FMNL2 activity has prometastatic effects in many types of tumors,” says Grosse. “In our current work, we could now demonstrate an important underlying process and a connection to the TGFbeta signaling pathway.”
According to the scientist, this knowledge could be used for tumor diagnostics or therapy. for example, by developing an antibody that indicates the presence of active FMNL2 or pharmacologically targets active, phosphorylated FMNL2.
Reference: “Vesicle-Associated Actin Assembly by Formins Promotes TGFβ-Induced ANGPTL4 Trafficking, Secretion and Cell Invasion” by Dennis Frank, Jessica Christel Moussie, Svenja Ulferts, Lina Lorenzen, Carsten Schwan and Robert Grosse, 24 January 2023, Advanced Science.
DOI: 10.1002/advs.202204896
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