Researchers reveal how cancer cells escape from tumors and spread

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A team led by associate professor Anand Asthagiri explores the biophysics behind the spread of breast cancer, providing hope for future treatments and early diagnosis. Photo by Mary Knox Merrill/Northeastern University

By Thea Singer

News at Northeastern

BOSTON–Metas­tasis. The very word evokes fear. Defined as the spread of cancer cells from one part of the body to another, metas­tasis is the cause of approx­i­mately 90 per­cent of deaths among cancer patients. How does metas­tasis come about? And can we stop it?

A team led by associate professor Anand Asthagiri explores the biophysics behind the spread of breast cancer, providing hope for future treatments and early diagnosis. Photo by Mary Knox Merrill/Northeastern University
A team led by associate professor Anand Asthagiri explores the biophysics behind the spread of breast cancer, providing hope for future treatments and early diagnosis. Photo by Mary Knox Merrill/Northeastern University

New research from a team led by Northeastern’s Anand Astha­giri, asso­ciate pro­fessor of bio­engi­neering and chem­ical engi­neering, helps to answer those ques­tions. It pro­vides an aston­ishing look at the bio­phys­ical prop­er­ties that permit breast cancer cells to “slide” by obsta­cles and travel out of their pri­mary tumor toward a blood vessel that will carry them to a new site.

The paper, pub­lished Tuesday in Bio­phys­ical Journal, reveals how the abnormal protein-fiber scaf­folding of tumors and the agility of the cancer cells them­selves come together in a per­fect storm to enable the escape. The quan­ti­ta­tive method the researchers devel­oped to under­stand the cells’ sliding ability could also lead to a new way to screen for effec­tive cancer drugs and help diag­nose the stage of a cancer early on.

We were showing that there are dif­ferent levels of sliding ability, and we mea­sured each one.”
— Anand Astha­giri, asso­ciate professor

We are looking at the inter­ac­tion between cancer cells’ migrating and this sliding phe­nom­enon, and how that’s influ­enced by the protein-fiber envi­ron­ments of tumors,” says Astha­giri. “In this paper we show that cancer cells migrating on these pro­tein fibers have a unique ability that enhances their inva­sion capacity: When they bump into other cells—which the microen­vi­ron­ment is packed with—they slide around them. Normal cells halt and reverse direction.”

An inter­dis­ci­pli­nary approach

The researchers’ engi­neering back­grounds shaped their inter­dis­ci­pli­nary approach: They set out to explore the mechanics of the sliding ability as well as its mol­e­c­ular components.

To do so they devel­oped a model envi­ron­ment that mimics pro­tein fibers. First they stamped stripes of a pro­tein called fibronectin on glass plates, making sure to rep­re­sent var­ious widths. “If you treat a fiber as a cylinder, imagine cut­ting it and opening it up and laying it flat,” says Astha­giri. “That’s essen­tially what these long stripes of pro­tein mim­icked.” Then they deposited the cells—alternately hun­dreds of breast cancer cells and hun­dreds of normal cells—on these fiber­like stripes and used a micro­scope with time-lapse capa­bil­i­ties to observe and quan­tify their behavior.

On fibers that were 6 or 9 microns wide—the typ­ical size of fibers in tumors—half the breast cancer cells elon­gated and slid around the cells they col­lided with. Con­versely, 99 per­cent of the normal breast cells did an about face.

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Source: Milano et al./Biophysical Journal 2016

But why? To under­stand what gave the cancer cells this remark­able agility, Astha­giri and his col­leagues, who included Daniel F. Milano, a former grad­uate research assis­tant at North­eastern, intro­duced “genetic per­tur­ba­tions” into the mix—that is, they inserted cer­tain pro­teins into the cancer cells and took the same pro­teins out of the normal cells. Among them was E-cadherin, a sticky pro­tein that enables cells to bind to one another.

Cancer cells often lack E-cadherin,” says Astha­giri. “When we intro­duced it genet­i­cally, the cancer cells’ ability to slide dimin­ished. And when we took E-cadherin out of normal cells, they acquired some sliding ability once the fibers were wide enough.” Together, the varying widths of the fiber paths and the per­tur­ba­tions pro­duced a wealth of quan­ti­ta­tive data about how the cells, both can­cerous and normal, behaved under dif­ferent conditions.

We weren’t just showing that cells either slide or don’t slide,” says Astha­giri. “We were showing that there are dif­ferent levels of sliding ability, and we mea­sured each one.”

Mul­tiple applications

Asthagiri’s system is rel­a­tively easy to con­struct and suited for rapid imaging—two qual­i­ties that make it an excel­lent can­di­date for screening new cancer drugs. Phar­ma­ceu­tical com­pa­nies could input the drugs along with the cancer cells and mea­sure how effec­tively they inhibit sliding.

In the future, the system could also alert cancer patients and clin­i­cians before metas­tasis starts. Studies with patients have shown that the struc­ture of a tumor’s protein-fiber scaf­folding can indi­cate how far the dis­ease has pro­gressed. The researchers found that cer­tain aggres­sive genetic muta­tions enabled cells to slide on very narrow fibers, whereas cells with milder muta­tions would slide only when the fibers got much wider. Clin­i­cians could biopsy the tumor and mea­sure the width of the fibers to see if that danger point were approaching. “We can start to say, ‘If these fibers are approaching X microns wide, it’s urgent that we hit cer­tain path­ways with drugs,” says Asthagiri.

Ques­tions, of course, remain. Do other types of cancer cells also have the ability to slide? What addi­tional genes play a role?

Next steps, says Astha­giri, include expanding their fiber­like stripes into three-dimensional models that more closely rep­re­sent the fibers in actual tumors, and testing cancer and normal cells together. “There are so many types of cells in a tumor environment—immune cells, blood cells, and so on,” he says. “We want to better emu­late what’s hap­pening in the body rather than in iso­lated cells inter­acting on a platform.”

(Published with permission from News at Northeastern.)

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