Gene regulation in mammals offers clues connecting pregnancy and cancer metastasis
Regulatory sequences in the genomes of mammals, including cows, pigs,
horses, and humans, help explain how normal tissue is invaded by cancer

Date:
February 7, 2022
Source:
University of Connecticut
Summary:
In many mammals including humans, the placenta invades the
wall of the uterus during pregnancy in the same way that cancer
cells invade surrounding tissues. Using genomic sequences and
gene expression information, researchers were able to predict
specific signaling proteins that drive the expression of genes
that decrease the susceptibility of invasion in human cells. Using
a custom fabricated bio chip, the researchers confirmed that these
predicted proteins did in fact decrease the invasion of both cancer
and placental cells.



FULL STORY ========================================================================== Researchers from UConn Heath and Yale University have made new advances connecting the evolution of pregnancy and cancer metastasis.


========================================================================== Publishing in the Proceedings of the National Academy of Sciences,
Yasir Suhail, a postdoctoral researcher working alongside Kshitiz,
assistant professor in the Department of Biomedical Engineering,
uncovered regulatory sequences in the genomes of mammals including cows,
pigs, horses, and humans that explain how endometrium is invaded by the placenta, and how normal tissue is invaded by cancer.

Suhail and Kshitiz were joined in their efforts by Gunter Wagner,
professor in evolutionary biology and ecology at Yale University.

In many mammals including humans, the placenta invades the wall of
the uterus during pregnancy in the same way that cancer cells invade surrounding tissues.

"When you look at a picture of placentation, it looks eerily similar to
cancer in any other part of the body," says Kshitiz, "Even the molecular mechanisms are quite similar. This is quite a contrast from cows and
horses, where the placenta does not invade into the mother. In these
mammals, cancer cells also do not invade into their surroundings as they
do in humans." Kshitiz, along with Gunter Wagner and Andre Levchenko
at Yale first drew the comparison between cancer metastasizing in cows
and humans in a seminal finding in Nature Ecology & Evolution. Looking
at cells from the endometrium of various species, Kshitiz found that in
order to resist invasion of the placenta, certain species have evolved
over time to make their stromal cells -- the connective tissue cells in
an organ -- highly resistant to any invasion.

The latest research is a deeper dive into the comparative genetics
between mammals, which shows how changes in genetic regulation informs
this resistance in cows and horses and makes humans vulnerable to
cancer malignancy. With comparative data generated by Wagner and Jamie
Maziarz at Yale, Suhail developed a model to identify how the binding
of transcription factors -- the proteins that regulate the expression
of genes -- explain changes in resistance to invasion across different
species of mammals.

"Our new framework identifies key transcription factors and examines
how their targets differ from cows, pigs, and horses to humans," says
Suhail. "What we learned from other species has direct applications
in advancing our understanding of human cancer." Suhail used the
genomic sequences and gene expression information to predict specific
signaling proteins that drive the expression of genes that decrease the susceptibility of invasion in human cells. Using a custom fabricated
bio chip, the researchers were able to confirm that these predicted
proteins did in fact decrease the invasion of both cancer and placental
cells. Evolutionary predictions across species are difficult to test experimentally, so confirmation of the theory experimentally is very
satisfying to the researchers.

"We all think about human cancers are an outcome of cancer cells
themselves.

But what we've proposed is that mammals have very different mechanisms
to resist cancer spread, and that these mechanisms have actually been
derived to resist fetal invasion into the mother," Kshitiz says. "To
be vulnerable to malignancy may partly be an evolutionary compromise
to allow an invasive pregnancy." While other researchers are targeting
cancer and immune cells, Kshitiz's lab focuses on how healthy cells limit cancer growth around them. This approach can help us rethink the way we approach cancer therapies.

"This study identifies specific genetic regulatory mechanisms which
explain these differences, and point us towards many directions to
rethink about anti- cancer therapy, from those that kill cancer to
creating new therapies which "contain" cancer within its boundaries." ========================================================================== Story Source: Materials provided by University_of_Connecticut. Original
written by Courtney Chandler. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Yasir Suhail, Jamie D. Maziarz, Ashkan Novin, Anasuya Dighe, Junaid
Afzal, Gunter Wagner, Kshitiz. Tracing the cis-regulatory
changes underlying the endometrial control of placental
invasion. Proceedings of the National Academy of Sciences, 2022;
119 (6): e2111256119 DOI: 10.1073/pnas.2111256119 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220207135831.htm

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