Study finds how NF-2 gene mutations make cells hyper-responsive to growth factor signaling

August 28, 2018

A team of Massachusetts General Hospital (MGH) Cancer Center researchers has determined one way that mutations in a gene involved in a rare, hereditary cancer syndrome lead to out-of-control cellular proliferation. In their report published online in Genes & Development, the team describes finding how mutations in the NF2 (neurofibromatosis type 2) gene, which codes for the merlin protein, make cells hyper-responsive to growth factor signaling. In addition to neurofibromatosis type 2, a genetic disorder that induces the formation of numerous benign tumors throughout the nervous system, NF2 mutations have also been associated with the dangerous malignant cancer mesothelioma.

"We have found that NF2-mutant cells of multiple types - including cells that initiate nervous system tumors in familial NF2 and mesothelioma cells with the NF2 mutation - excel at a natural process cells use to gulp up and internalize fluids from their environment, as if they were captured by a breaking wave," says Andrea McClatchey, PhD, of the MGH Center for Cancer Research, senior author of the paper. "This ability enables cells to respond excitedly to growth factors they normally might not detect and may allow NF2-mutant cells to survive and grow outside their normal milieu, ingesting extra nutrients that further fuel their inappropriate responsiveness to growth factors."

Merlin and related proteins are known to organize the interface between the plasma membrane that surrounds cells and the cytoskeleton, the internal network of fibers that gives cells their shape and structure. Membrane/cytoskeleton linkages both modulate the activity of receptor proteins located on the membrane and respond to receptor activation, but exactly how those interactions influence cellular behavior has not been well understood. Inappropriate activation of growth-factor receptors underlies many types of cancer, which has led to the proliferation of therapies that target specific growth factor pathways.

Under certain circumstances, the interface between the cell membrane and cytoskeleton can initiate a process called macropinocytosis, in which the cell membrane forms wave-like "ruffles" that reach out and engulf surrounding fluids, forming vesicles that are taken into the cell with their contents, including activated receptor proteins from the membrane. Macropinocytosis can be triggered by growth factor receptor activation and can influence the recycling of receptors back to the cell membrane. Recent studies have suggested that certain tumor cells use macropinocytosis to scavenge extra nutrients from their environment, helping to drive their growth.

In the current study, McClatchey's team focused on the epidermal growth factor receptor (EGFR), overactivation of which is involved in several important cancers. They had previously shown that the absence of merlin greatly increased cells' responsiveness to stimulation of the EGFR. The new experiments support a role for merlin in calming the cell membrane, keeping cytoskeletal response to growth factor activation under control. Several types of merlin-deficient NF2-mutant cells showed a magnified response to growth factors, with marked increases in ruffling of the membrane and in macropinocytosis.

The researchers also found that, in the absence of merlin, cholesterol accumulates in the cell membrane, promoting the recycling of receptors back to the membrane and further magnifying the growth factor response. Reducing membrane cholesterol levels in NF2-mutant cells limited this growth factor recycling and the resultant cellular overproliferation. This recycling of receptors, instead of increased ingestion of nutrients, appears to be the key result of elevated macropinocytosis in NF2-mutant tumors.

"Importantly, macropinocytosis is also a way that some drugs enter cells - particularly larger drugs than can't pass through the cell membrane," says McClatchey, who is a professor of Pathology at Harvard Medical School. "This implies that NF2-mutant cells, which are very good at macropinocytosis, may be particularly good targets for drugs that enter cells that way, in addition to being vulnerable to agents that modulate membrane cholesterol and receptor recycling. Early follow-up studies support this hypothesis. Important next steps will be to investigate whether NF2-mutant cells overreact to a broad range of growth factors by undergoing macropinocytosis, how NF2-deficient cells process internalized macropinocytic vesicles, and whether macropinocytosis can be exploited for delivering drugs to NF2-mutant tumors."
-end-
Christine Chiasson-MacKenzie, PhD, MGH Center for Cancer Research (MGH-CCR) and Department of Pathology, is the lead author of the Genes & Development paper. Additional co-authors - all of the MGH-CCR- are Zachary Morris, MD, PhD (now at the University of Wisconsin, Madison), Ching-Hui Liu, William Bradford and Thijs Koorman, PhD. Support for the study includes National Institutes of Health grants R01 CA113733 and T32 5T32CA009361-35; Department of Defense grant W81XWH-16-1-0086 and support from the Mesothelioma Applied Research Foundation. McClatchey is the 2011 Patricia and Scott Eston MGH Research Scholar.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $900 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2018 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."

Massachusetts General Hospital

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.