The Scientist - USA (2020-04)

04.2020 | THE SCIENTIST 47

KSHITIZ ET AL.,

NAT

ECOL EVOL

; PINAR MESCI

WELCOME M AT: Cow trophoblasts (green) invade a layer of human stromal

cells (black), which may also be susceptible to metastasizing cancer cells.

CANCER BIOLOGY

Another Break in the Wall

THE PAPER

Kshitiz et al., “Evolution of placental invasion and cancer

metastasis are causally linked,” Nat Ecol Evol, 3:1743–53, 2019.

The study was conceived like a cliché joke: an evolutionary biologist,

a cell-signaling specialist, and a cancer researcher walk into a happy

hour at Yale University. The conversation turned to mammalian

tumors, and how it was common to see horses in Austria and cows

in India with prominent tumors that rarely killed the animals.

It turns out that horses and cows have something else in common.

“Interestingly, in the same animals, the pregnancy is very different from

human pregnancy,” says the University of Connecticut Health Center’s

Kshitiz, the cancer researcher, who uses a single name. Placental cells

in ungulates don’t burrow into the uterine lining early in pregnancy as

they do in apes and many other mammals.

The researchers were not the first to draw a connection between

cancer severity—specifically, whether the tumors metastasize to

other locations in the body and become more deadly—and placental

invasion. But they wondered if the key to that link was the action

not of the invading cells, but of the tissue that was under attack.

Together with colleagues, the trio cultured layers of human or bovine

endometrial stroma cells and tested their resistance to invasion by

placental cells from both species and by a melanoma cancer cell line.

“The difference between cow and human was just like day and night,”

Kshitiz says. “The cow cells will resist invasion; the human cells will...

not only not resist, but may even assist invasion.”

“I think the most striking feature of this paper is that they

show that it’s not really the way in which the cancer cells behave

that’s different, but it’s really the fibroblasts—the stromal cells—

how they respond to the cancer cells,” says Karuna Ganesh, an

oncologist and cancer researcher at Memorial Sloan Kettering

Cancer Center. The finding suggests, she says, that healthy

fibroblast tissue could be targeted by therapeutics with the aim

of halting metastasis. That’s a possibility Kshitiz’s lab is already

exploring in follow-up work.

—Shawna Williams

SEEK AND DESTROY: The Zika virus was unable to enter patient-derived

glioblastoma stem cells (green) growing on a human brain organoid if the

cells lacked a particular integrin in their membranes.

DRUG DEVELOPMENT

Zika, Cancer Warrior?

THE PAPER

Z. Zhu et al., “Zika virus targets glioblastoma stem cells through a

SOX2-integrin αvβ 5 axis,”Cell Stem Cell, 26:187–204.E10, 2020.

In 2017, University of California, San Diego, regenerative medicine

researcher Zhe Zhu and colleagues found that the Zika virus, which

sparked a widespread epidemic in the Americas a few years ago and

is known to cause microcephaly in fetuses by destroying neural stem

cells, preferentially targets and kills glioblastoma stem cells (J Exp

Med, 214:2843–57). The researchers argued that a modified form of

Zika could potentially be used as an oncolytic virus therapy against

glioblastoma, an aggressive type of brain cancer.

Following up on that work, Zhu and collaborators set out to find “the

unique property of this virus” that allows Zika to selectively target brain

cancer stem cells while sparing adjacent tissues, says Zhu. Previous

research has shown that a number of viruses use integrins, a group of

transmembrane cell adhesion receptors, as gateways for entering host

cells. The team wondered whether the same was true of Zika.

Using antibodies, the researchers blocked different integrins in

brain cancer stem cells and found that the integrin αvβ 5 , which is

produced at higher levels in brain cancer tissue than in normal brain

tissue, seemed to be responsible for helping the virus enter the

cells. Silencing the same integrin in a brain cancer mouse model,

human brain organoids, and glioblastoma surgical samples also

blocked Zika infection.

Zhu and his collaborators believe that understanding Zika’s entry

mechanism can lead them closer to treatments for glioblastoma. “We

hope that we can eventually use this virus in clinical trials and help to

improve the outcome of the patient,” he says.

Hongjun Song, a neural stem cell researcher at the University

of Pennsylvania who was not involved in the study, agrees that a

modified version of the Zika virus is a potential therapeutic tool for

treating glioblastoma. The approach is still a long way from clinical

trials, Song says, “but this is a really interesting mechanistic study to

go towards that direction.”

—Amy Schleunes