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Asthagiri is Exploring the Spread of Cancer Cells

BioE Associate Professor Anand Asthagiri explores the biophysics behind the spread of breast cancer, providing hope for future treatments and early diagnosis.

Source: News @ Northeastern

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?

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.


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.”

Related Faculty: Anand Asthagiri

Related Departments:Bioengineering