UTSW researchers find form drives function in cancer proliferation

UTSW researchers find form drives function in cancer proliferation

DALLAS – May 7, 2019 – A new study finds that the protein responsible for the crawling movements of cells also drives the ability of cancer cells to grow when under stress.

The protein
is actin, which is also a key component of the contraction apparatus of muscles
throughout the body. The link between cell movement and signaling is through
the cell’s actin cytoskeleton – chains of actin that dynamically
assemble and disassemble to aid locomotion in cancerous and noncancerous cells.

Although the actin cytoskeleton was known to be involved in the spread, or metastasis, of cancer cells, the fact that the cell migration machinery can drive cancer cell growth has never before been described, said Dr. Gaudenz Danuser, UT Southwestern Chair of the Lyda Hill Department of Bioinformatics and Professor of Bioinformatics and Cell Biology.

Dr. Danuser
is the corresponding author of the study published today in Developmental Cell
that identifies a novel role for actin in cell signaling.

The study
demonstrates that form drives function in a mechanism that behaves one way in
both noncancerous cells and in unstressed cancer cells but acts differently in
cancer cells that encounter stressors such as chemotherapy or the need to adapt
to a new environment such as after spreading from the skin to lung tissue. When
encountering such stresses, the actin mechanism affects signaling to promote
drug resistance or aggressive metastatic growth.

In the
paper, the researchers point out that drug resistance and metastasis represent

“two of the
most critical factors in determining prognosis for cancer patients.”

In their
studies, the researchers took human skin cancer (melanoma) cells that contained
a mutation in the Rac1 gene linked to chemotherapy-resistant tumors and used
CRISPR/Cas9 gene editing to snip out the single-base pair mutation and revert
it to the normal gene. The scientists found that in a petri dish, cells with
the mutation continued to grow when exposed to chemotherapy, while cells with
normal Rac1 could not – even though both kinds of cells remained cancerous.
When injected into mice, cells carrying the mutation made much larger
metastatic nodules than cells carrying the normal version of the gene.
Interestingly, cancer cells with or without the mutation grew at the same rate,
as long as they were not exposed to chemotherapy or remained in the primary
tumors. Hence, it is the stress of a new environment that turns on cell growth
in the mutated cells, the researchers said.

In 2012,
laboratories at Yale and at MD Anderson Cancer Center independently isolated
the Rac1 mutation in melanoma. About 10 percent of melanoma patients carry the
mutation.

“In 2014,
the MD Anderson group showed that this mutation is among the culprits behind
chemotherapy resistance in skin cancer cells,” said study lead author Dr.
Ashwathi (Abbee) Mohan, who recently received her Ph.D. from the Cancer Biology
Graduate Program and UT Southwestern’s Medical Scientist Training Program. The
UTSW study identifies for the first time a reason for the mutation’s ability to
encourage drug resistance and the growth of cancer cells – and it’s a
structural one.

By combining
gene editing, molecular cell biology, advanced live-cell imaging, and computer
vision, they show that when cells with the Rac1 mutation are stressed, the
actin cytoskeleton creates enlarged sheet-like protrusions – called
lamellipodia from the Greek for “thin sheet” and “foot.” Noncancerous cells or
cancer cells without the mutation extend much smaller lamellipodia to initiate
migration. “These sheets – lamellipodia – (in stressed cancer cells that have
the mutation) are so massive that they sequester and turn off tumor suppressor
molecules, which otherwise would control cell growth,” Dr. Mohan said.

“It
resembles catching the signaling molecules in a net. This raises the
possibility of restoring the chemotherapy response by blocking the assembly of
these dense actin sheets,” Dr. Mohan added. “It’s almost like a superpower that
some cancer cells have that makes them able to resist drugs and to grow more
aggressively after spreading to different parts of the body.”

Dr. Danuser
agreed, saying,

“Our data
reveal that beyond roles in controlling cell shape and enabling cell migration,
the actin cytoskeleton is also actively involved in regulation of cell
signaling. This research opens the door to better understanding how a cell uses
the actin cytoskeleton for coupling the control of shape and signals in both
normal and cancerous processes. More specifically, it is possible that through
this mechanism, dysregulation of Rac1 signals plays a much bigger role in
cancer progression than so far appreciated.”

The Danuser lab is now working to better understand how cancer cells know when to turn on and off this form-driven signaling machinery.

“It is clear
that with this machinery, cancer cells are able to turn on and off a growth
pathway instantaneously,” said Dr. Danuser, holder of the Patrick E. Haggerty
Distinguished Chair in Basic Biomedical Science. “If we can figure out how the
cells access this pathway, we can block what we have found to be a critical
escape route that cancer cells use to resist drug treatment.”

“This study
reaffirms the concept that cell shape is instrumental in driving signaling –
that by simply spreading out, cell signals can be silenced and sequestered.
Cancer exploits this ability to drive both drug resistance and metastasis,” he
added.

UTSW
co-authors include Assistant Professor Dr. Kevin Dean and Senior Research
Scientist Dr. Dana “Kim” Reed, both of Cell Biology; Assistant Professor Dr.
Jungsik Noh, Instructor Dr. Erik Welf, and postdoctoral researchers Dr.
Tadamoto Isogai, Dr. Vasanth Murali, and Dr. Philippe Roudot, all of
Bioinformatics; and Stacy Kasitinon of the Children’s Medical Center Research
Institute at UT Southwestern (CRI). Scientists from UC San Diego and Michigan
Technological University also participated in the study.

The study
received funding from the National Institutes of Health, the Human Frontier
Science Program, and The Welch Foundation.

About UT
Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the USA, integrates pioneering biomedical research with exceptional clinical care and education.

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