The Scientist - USA (2020-04)

18 THE SCIENTIST | the-scientist.com

Ganesh and her colleagues decided

to use the organoids, along with experi-

ments in mice, to probe for factors that

caused relatively mild-mannered tumor

cells to switch on L1CAM and other genes

needed to initiate metastasis. What they

found, she says, is that the tumor’s phys-

ical environment plays a role in tilting

cancer cells toward striking out to colo-

nize new territory.

The colon is made of epithelial tis-

sue, meaning that its cells grow in sheets,

Ganesh explains. Colon cells “like to be

attached to their neighbors, and when they

let go of their neighbors, they are designed

to die.” A key finding of the new study, she

says, is that the metastasis-inducing can-

cer cells respond to physical detachment

from surrounding cells not by under-

going apoptosis, but by gaining new abil-

ities—a phenomenon that the team also

detected in cells that regenerate tissue

after wounding. Specifically, the team

identified L1CAM expression in a special-

ized population of cells in mice with colitis

that appeared to use the protein to facili-

tate healing of damage to the colon caused

by inflammation. By contrast, levels of

L1CAM RNA were negligible in the colon

epithelia of control mice without colitis

(Nat Cancer, 1:28–45, 2020).

Both the regenerative cells and the

metastasis-initiating cells switch on

L1CAM as they change to a mode in

which they can survive without their

neighbors. In the case of the metasta-

sizing cells, Massagué says, the team’s

recent study indicates that the protein

allows them to seek out and adhere to

a membrane that surrounds capillaries

at sites of future metastasis. Once it’s

latched on, L1CAM signals the cells to

begin proliferating. But Massagué adds

that it’s just one of the proteins enabling

metastasis; he plans to investigate the

actions of others as well, in hopes of

finding additional therapeutic targets.

While L1CAM has long been recog-

nized as a metastasis marker, “actually

effectively targeting and linking it to the

changes in the epithelial status of the

tumor, I think, are very interesting,” says

David Menter, a gastrointestinal cancer

researcher at MD Anderson Cancer Cen-

ter who was not involved in the study. “It

provides new avenues for us to think about

targeting metastasis.”

Another recent paper by Massa-

gué and colleagues similarly identi-

fies likenesses between metastasizing

and regenerating cells in the lung (Nat

Med,  26:259–69, 2020). For Judith

Agudo, a cancer immunologist at the

Dana-Farber Cancer Institute who was

not involved in the work, a key take-

away of these studies is that “they bring

this new angle in which metastasis takes

advantage of pathways that take place in

the body during wound healing or regen-

eration, which can explain a lot [about]

how metastasis works. And that new

view was really interesting.”

For his part, Ben-Ze’ev feels that the

new study is sound, but says some of its

findings echo insights about L1CAM and

colon cancer progression and metastasis

that were previously reported by his group

and others—a viewpoint he lays out in a

review on the site F1000.

In Ganesh’s view, the study high-

lights the importance of using models for

drug discovery that include metastasis-

capable cells. “Many of the models that

people used for drug discovery actually

don’t contain this metastasis stem cell

state,” she says, but rather consist of mice

with benign tumors. “If you want to treat

metastasis with drugs that treat meta-

static cancer, which is ultimately what

all cancer drugs are, then we really need

to have model systems that capture this

metastasis stem cell state.”

—Shawna Williams

Blasting

Through

Biofilms

When Kevin Braeckmans and To m Coe-

nye first teamed up in 2009 to devise

new ways to treat badly infected wounds,

it seemed like a natural pairing. Braeck-

mans was a drug delivery expert with

no microbiology experience, while Coe-

nye was a microbiologist lacking drug

delivery expertise. These two research-

ers, both at Ghent University in Belgium,

aspired to outfox biofilms—cooperative

clusters of bacteria that infect 90 per-

cent of chronic wounds and stymie many

antibiotics due to their sticky, tightly

packed nature.

The standard therapy for biofilm-

afflicted wounds is to scrape away

infected tissue before the infection

becomes lethal. But after four years of

working on an alternative to this pain-

ful and sometimes ineffective approach,

Braeckmans and Coenye were stuck.

They had learned how the electrical

charges and molecular sizes of antibiotic

compounds affected the drugs’ move-

ments through biofilms. And with that

information, they had managed to get

antibiotics deep into biofilms by pack-

aging them into appropriately sized and

shaped nanoparticles, which help ferry

small compounds a bit like a taxi shut-

tles passengers, says Braeckmans. It still

wasn’t enough.

“We could get the drug molecules into

the taxi [and] the taxi could drive inside

the biofilm. That was not a problem,”

Braeckmans recalls. “But we could not get

the passengers out again.”

So in 2014, the scientists started to test a

different approach. Instead of incorporating

drugs into nanoparticles, they tried perco-

lating gold nanoparticles into biofilms and

zapping them with pulses of yellow-green

laser light. These zaps rapidly heat the

particles and the water enveloping them,

creating vapor nanobubbles. When these

bubbles implode, they create high-energy

shock waves that tear the biofilm’s structure

and clear passageways for antibiotics.

NOTEBOOK

Laser-triggered nanobubbles

were often as effective at

aid ing antibiotic delivery as

breaking up bio films using

sound or stirring.