How mechanical forces nudge tumors toward malignancy

Date:
September 2, 2020
Source:
Rockefeller University
Summary:
Researchers studying two forms of skin cancer identified a long-
overlooked factor determining why some tumors are more likely to
metastasize than others: the physical properties of the tissue in
which the cancer originates. The findings might set the stage for
new ways to monitor and treat the diseases in the future.



FULL STORY ==========================================================================
All cancers are the result of cells that have gone haywire, multiplying
out of control and expanding beyond their normal constraints. But not
all tumors are the same: for reasons that remain poorly understood, some
are more likely to become aggressive and metastasize to other parts of
the body.


==========================================================================
New research highlights a long-overlooked aspect of how and why some
tumors become more dangerous than others. A team led by Rockefeller's
Elaine Fuchs found that mechanical properties of the tissue elements that surround pre- malignant tumor cells powerfully shape the development of
two of the most common forms of skin cancer, causing one to become far
more aggressive and invasive than the other.

The work, published recently in Nature, may eventually help clinicians
predict how a particular tumor will evolve and could lead to novel
anti-cancer therapies.

Not so simple The researchers focused on two types of tumors that
originate within stem cells in the skin known as epidermal stem cells:
basal cell and squamous cell carcinomas, the latter of which tends to be
much more aggressive and dangerous than the other. The two tumor types
also possess highly distinctive structures and appearances: basal cell carcinomas originate as bud-like clusters of cells, while squamous cell carcinomas begin as tiny folds in the skin tissue.

Led by postdoctoral fellow Vince Fiore in the laboratory of Elaine
Fuchs, the team induced each type of tumor in two different groups of genetically engineered mice, and then measured their physical properties
and that of the surrounding tissue. Collaborating with researchers
at Princeton University, they also constructed computer models of the
epidermis that accurately simulated how the tumors arose and acquired
their characteristic shapes.



========================================================================== Previous research had shown that in simple, single-layer tissues such
as those found in the gut, tumors develop and change shape largely
in response to the rapid proliferation of cancer cells and the forces
they exert as the cells push and pull on one another. But the team's
computer simulations showed that these factors cannot generate the
distinctive shapes and structures of basal and squamous cell carcinomas
that form within more complex, multilayered tissues like the epidermis --
a suggestion that was borne out by experiments on the mice.

So the team set about looking for other culprits that could in fact
produce the two distinct tumor types.

A rock and a hard place By analyzing differences in gene expression
between the two types of tumors, Fiore and his colleagues identified
a set of genes that play a critical role in setting the physical
properties of the basement membrane, a thin dense layer of intertwined
proteins secreted by the stem cells of the epidermis and its developing
tumors. "The basement membrane acts as a kind of floor that separates
the tumor from the surrounding tissue," Fiore explains.

Computer modeling predicted that softening the basement membrane or
increasing the rate at which it is assembled would generate the buds characteristic of basal cell carcinomas. Stiffening the membrane or
slowing down its assembly rate, on the other hand, would cause the
folding associated with squamous cell carcinomas.



==========================================================================
To test those predictions, the researchers manipulated the expression
of the genes in their lab animals, altering the stiffness and assembly
rate of the basement membrane in various ways. The simulations proved
correct: changing the mechanical properties of the basement membrane
did in fact influence both the shape and behavior of basal and squamous
cell carcinomas.

"In each case, what we predicted would happen indeed happened,"
Fiore says.

Further experiments revealed that basal and squamous cell carcinomas
aren't just shaped by the physical properties of the floor beneath
their feet, however. Their structure and behavior are also influenced
by the stiffness of the roof over their heads: the layers of so-called suprabasal cells that lie directly above them.

Squamous cell carcinomas are characterized by a relatively stiff
suprabasal roof, making it more likely that the tumors will eventually
break through the basement membrane floor, escape into deeper layers
of the skin, and ultimately spread throughout the body. Basal cell
carcinomas, whose suprabasal roof is less rigid, are more likely to stay
put, rendering them more benign.

"Because epidermal stem cells make both basement membrane and overlying suprabasal cells, they control the tissue's architecture," says Fuchs,
who is Rockefeller's Rebecca C. Lancefield Professor. "However, as stem
cells acquire cancer-inducing mutations that change their program of
gene expression, they begin to lose control of the mechanical properties
needed to keep the tissue fit and healthy." By identifying some of
the genes that shape tumor development, the research could someday
help clinicians predict whether a particular tumor is likely to become dangerously aggressive -- and provide targets for drugs that might
prevent that from happening.

"With these principles in mind, you can begin to understand how tumors
become malignant, and then use that knowledge to perform risk assessment
or develop new therapies," Fiore says.


========================================================================== Story Source: Materials provided by Rockefeller_University. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Vincent F. Fiore, Matej Krajnc, Felipe Garcia Quiroz, John
Levorse, H.

Amalia Pasolli, Stanislav Y. Shvartsman, Elaine Fuchs. Mechanics
of a multilayer epithelium instruct tumour architecture and
function. Nature, 2020; DOI: 10.1038/s41586-020-2695-9 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200902182436.htm

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