The Scientist - USA (2022 - Spring)

SPRING 2022 | THE SCIENTIST 65

EDITOR’S CHOICE IN GENETICS

Pregnancy Pressure

THE PAPER

M. Tesfaye et al., “Impact of depression and stress on placental DNA

methylation in ethnically diverse pregnant women,” Epigenomics,

13:1485–96, 2021.

The mental health of pregnant people can influence the development

and health of their children who are still in utero, though the molecu-

lar mechanisms linking maternal depression or stress and fetal out-

comes remain unclear. As part of a broader study on fetal growth, the

National Institutes of Health (NIH) assessed maternal mental health

through questionnaires administered between 2009 and 2013 to more

than 300 ethnically diverse women at six points during their pregnan-

cies, and coupled these data with placental tissue samples collected

shortly after delivery.

Examining the association between the survey responses and pla-

cental DNA methylation, NIH genetic epidemiologist Fasil Tekola-Ayele

and colleagues found that maternal depression was correlated with 16

distinct methylation sites, while stress was linked to another two sites.

Furthermore, methylation at two of the depression-linked sites was

significantly associated with changes in the expression of ADAM23 and

CTDP1, genes implicated in neurodevelopment and psychiatric condi-

tions such as schizophrenia and bipolar disorder.

The authors say that the strength of the study lies in its use of an

ethnically diverse cohort to identify placental methylation sites pos-

sibly related to fetal neurodevelopment. “When the problem involves

diverse groups, the study should also mirror that demographic,” Tekola-

Ayele says. “Scientific advances... and the benefits in terms of health

that come out of it [will] reach wider population groups when we start

with diverse and representative samples.”

Thomas O’Connor, a University of Rochester Medical Center clinical

psychologist who was not involved with the study, hopes the research-

ers will “extend this to see how those changes in placental DNA meth-

ylation map onto—or not—child health outcomes.” He adds that while

using placentas in health diagnostics is not yet “actionable,” the work

suggests it may be in the future.

—Chloe Tenn

MATERNAL STRESS: Methylation at certain sites in placental DNA were

associated with depressive feelings and stress in pregnant women.

MODIFIED FROM © ISTOCK.COM, VLADIMIR KONONOK; NATIONAL CANCER INSTITUTE, UNIVERSITY OF PITTSBURGH CANCER INSTITUTE

THE LITERATURE

EDITOR’S CHOICE IN CANCER

Starving Cancer

THE PAPER

G. Salvadori et al., “Fasting-mimicking diet blocks triple-negative breast

cancer and cancer stem cell escape,” Cell Metab, 33:2247–59, 2021.

Triple-negative breast cancer is one of the most aggressive breast can-

cers because of its resistance to treatments. However, recent studies

have shown that fasting-mimicking diets—which include roughly 50

percent fewer calories and reduced proteins and sugars compared to

average diets—can slow tumor growth.

Giulia Salvadori, a postdoc at the FIRC Institute of Molecular

Oncology (IFOM) in Italy, studied the mechanism behind how fast-

ing affects tumors in biogerontologist Valter Longo’s lab. Their team

experimented with cancer stem cells, both those cultured on nutrient-

poor substrates and those in mice given a fasting-type diet. The results

showed that lower glucose levels in the nutrient-poor conditions down-

regulated protein kinase A, an enzyme that promotes cancer cell growth

and spread. This resulted in fewer and smaller tumors and longer

mouse survival.

Cancer cells that had already differentiated into mature tumor

cells in mice, however, adjusted metabolically to low glucose, activat-

ing alternate “starvation escape pathways” to survive. Longo explains

that “if you have the fasting-mimicking diet, the cancer rewires and just

finds a few ways to stay alive.” But this behavior presents therapeutic

opportunities too: “If you block those [pathways], then it’s in trouble.”

Indeed, treating mouse tumors with a three-drug combination paired

with a restricted diet killed cancer cells while avoiding damage to non-

cancerous cells, findings that Salk Institute molecular biologist Satchin

Panda, who was not involved in the work, calls “really impressive.”

The study also examined retrospective data from 81 triple-negative

breast cancer patients and found that lower blood glucose levels cor-

related with higher survival rates, though Longo notes the need for

clinical trials to validate the effect. If the combination treatment was

also successful in humans, Panda adds, researchers “[wouldn’t] have

to make a new drug discovery,” but could instead use “existing drugs

to improve survival.”

—Devin A. Reese

SUGAR CRASH: A triple-negative breast cancer cell undergoing cell death

following drug treatment (actin in red, mitochondria in green, cell nuclei

in blue)