JACKSONVILLE, Fla.— Like a car with a front and back end, a steering mechanism and an engine to push it forward,
cancer cells propel themselves through normal tissues and organs to spread cancer throughout the body. Researchers at Mayo Clinic in Florida, however, have managed to turn these cells into shapes like a round fried egg and an exaggerated starfish that sticks out in many directions — both of which cannot now move.
In research published in the December issue of Molecular and Cellular Biology, investigators reveal how interplay of molecules keeps cancer cells moving forward, and how disturbing the balance of these proteins pushes their shape to change, stopping them in their tracks.
Investigators say they have already identified a number of agents — some already used in the clinic for different disorders — that may force shape-shifting in tumor cells.
“We are starting to understand mechanistically how cancer cells move and migrate, which gives us opportunities to manipulate these cells, alter their shape, and stop their spread,” says the study’s lead investigator, Panos Z. Anastasiadis, Ph.D., chair of the Department of Cancer Biology at Mayo Clinic in
“It is the spread — the metastasis — of cancer that is largely responsible for the death of cancer patients, so stopping these cells from migrating could potentially provide a treatment that saves lives,” he says.
The study was conducted using tumor material from breast and brain (glioblastoma) cancer. Both of these tumors are generally lethal when they spread — breast to other organs, and brain cancer as it crawls throughout the brain.
The researchers found that a protein called Syx is key to determining how tumor cells migrate.
When researchers removed Syx from the cancer cells, they lost their polarity — their leading and trailing edges — and morphed into the fried egg shape. “They are now unable to sense direction, so they are not going anywhere,” Dr. Anastasiadis says.
The team of scientists then identified the biological mechanism that caused this shape-shift. They found that two important molecules — ROCK and Dia — have to be in balance for tumor cells to establish polarity. Too much ROCK or too little Dia creates the fried egg shape. Too much Dia or too little ROCK creates a cancer cell with many front and back edges — like the starfish. And the researchers discovered that Syx works by regulating Dia.
Therapeutics that could induce shape-shifting in cancer cells may already be available, Dr. Anastasiadis says. ROCK inhibitors are being tested for pulmonary hypertension, among other conditions.
And, in previous research, Dr. Anastasiadis and his team discovered several other kinase inhibitors that can
turn off Syx.
“We plan to unravel the whole pathway that regulates how cancer cells sense their environment and move,” he says. “If we can identify all the components — akin to the steering, transmission, gas pedal and brake of a moving car -- we can also pick the best way to halt its movement.”
All of the study authors are from the Department of Cancer Biology at the Mayo Clinic Comprehensive Cancer Center
in Florida. They include Justus C. Dachsel, Ph.D., Siu P. Ngok, Ph.D., Laura J. Lewis-Tuffin, Ph.D., Antonios Kourtidis, Ph.D., Rory Geyer, Ph.D., Lauren Johnston and Ryan Feathers.
The study was supported by National Institutes of Health grants R01 NS069753 and R21 NS070117.