Nav: Home

Form drives function in cancer proliferation

May 06, 2019

DALLAS - May 6, 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.
-end-
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 nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

UT Southwestern Medical Center

Related Cancer Articles:

Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Cancer genomics continued: Triple negative breast cancer and cancer immunotherapy
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Metabolite that promotes cancer cell transformation and colorectal cancer spread identified
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
UH Cancer Center researcher finds new driver of an aggressive form of brain cancer
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
UH Cancer Center researchers develop algorithm to find precise cancer treatments
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
New analytical technology to quantify anti-cancer drugs inside cancer cells
University of Oklahoma researchers will apply a new analytical technology that could ultimately provide a powerful tool for improved treatment of cancer patients in Oklahoma and beyond.
Radiotherapy for lung cancer patients is linked to increased risk of non-cancer deaths
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Cancer expert says public health and prevention measures are key to defeating cancer
Is investment in research to develop new treatments the best approach to controlling cancer?
UI Cancer Center, Governors State to address cancer disparities in south suburbs
The University of Illinois Cancer Center and Governors State University have received a joint four-year, $1.5 million grant from the National Cancer Institute to help both institutions conduct community-based research to reduce cancer-related health disparities in Chicago's south suburbs.
Leading cancer research organizations to host international cancer immunotherapy conference
The Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research will join forces to sponsor the first International Cancer Immunotherapy Conference at the Sheraton New York Times Square Hotel in New York, Sept.

Related Cancer Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Anthropomorphic
Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#532 A Class Conversation
This week we take a look at the sociology of class. What factors create and impact class? How do we try and study it? How does class play out differently in different countries like the US and the UK? How does it impact the political system? We talk with Daniel Laurison, Assistant Professor of Sociology at Swarthmore College and coauthor of the book "The Class Ceiling: Why it Pays to be Privileged", about class and its impacts on people and our systems.