According to a recent study by researchers from the University of Pennsylvania’s Perelman School of Medicine, a stress protein that is overactive in several types of tumour cells also plays an important role in tumor-supporting cells called fibroblasts and may be a good target for cancer treatment in the future.
The researchers revealed that the stress protein known as ATF4 allows fibroblasts to assist tumour development by encouraging the production of tumor-serving blood vessels in trials using mice models of pancreatic cancer and melanoma.
The researchers discovered that deleting ATF4 in fibroblasts greatly hindered new tumor-supportive vasculature creation as well as tumour development without causing major damage to the animals. “Our findings show that suppressing ATF4 might be effective against many forms of cancer,” said research senior author Constantinos Koumenis, PhD, the Richard H. Chamberlain Professor of Research Oncology in Penn’s Department of Radiation Oncology. “Every tumour we’ve examined upregulates ATF4”
Ioannis Verginadis, PhD, a senior research scientist and adjunct assistant professor at Koumenis’ laboratory, was the study’s primary author and performed the majority of the experiments.
ATF4 is generated in cells as part of a broader response to stressors such as a lack of oxygen or nutrients. It acts as a master switch for hundreds of genes that help cells withstand various shocks. Many tumour forms, as demonstrated by Koumenis’ research and others in recent years, rely on this ATF4-associated stress response to survive despite the high stressors created by their fast development.
The new study began with the researchers developing mice whose ATF4 gene may be removed body-wide at any time. They discovered that deleting ATF4 before or even after tumours began to develop in mice dramatically reduced tumour growth and potential to disseminate to distant organs.
The researchers then used a powerful and relatively new technique known as single-cell RNA sequencing to investigate the impact of ATF4 deletion in all cell types within the tumour – and discovered a strikingly large effect on a population of tumor-supporting cells known as cancer-associated fibroblasts (CAFs).
Fibroblasts are support cells found in almost all organs that produce the crucial structural protein collagen, promote new blood vessel creation, and help with tissue repair and maintenance in general. Many tumour types coax neighbouring fibroblasts into CAF mode, where they primarily assist the tumour. However, the researchers discovered that in ATF4-deficient mice, CAFs frequently lacked activation signals and were faulty in making collagen and secreting chemicals that stimulate new artery formation.
As a result, quantities of collagen and tumor-supplying blood vessels were drastically decreased within the mouse tumours, resulting in massive tumour cell death.
When the scientists removed ATF4 exclusively in fibroblasts, they detected a tumor-slowing impact that was almost as significant as the full-body ATF4 deletion. The growth-slowing impact of ATF4 deletion was significantly reversed when the researchers introduced normal, ATF4-containing fibroblasts to ATF4-deficient animals.
“These findings suggest that ATF4’s support for malignancies is mostly mediated by CAFs,” Verginadis added.
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The researchers discovered a substantial link between indicators of ATF4 activity and markers of collagen formation in tumour tissue from human pancreatic cancer and melanoma patients, highlighting the possible applicability of their findings to human malignancies.
Furthermore, in melanoma instances, increased collagen synthesis was associated with a worse prognosis.
The researchers are optimistic that targeting ATF4 will not result in undesirable side effects because adult mice with the gene removed exhibited only slight and transitory weight loss and other minor problems.
“Overall, ATF4 looks to be an appealing cancer target,” Koumenis added. “A treatment that inhibits it would decrease its pro-tumor action not just in tumour cells but also in cancer-associated fibroblasts, giving the tumour a double whammy. But that is still a few years away.”
Koumenis’ group is currently attempting to create ATF4 inhibitors that may be evaluated in future animal experiments and, eventually, in human cancer patients. The National Institutes of Health funded the study.
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