A stress protein that is overactive in many types of tumor cells also plays a key role in tumor-supporting cells called fibroblasts, and could be a good target for future cancer treatments, a study by researchers suggests from Perelman School of Medicine at the University of Pennsylvania.
The researchers, whose findings seem in Cell Biology Nature, found in experiments in mouse models of pancreatic cancer and melanoma that the stress protein, known as ATF4, enables fibroblasts to support tumor growth by promoting the formation of blood vessels serving to the tumor. Deleting ATF4 in fibroblasts severely impaired the formation of new tumor-supporting vessels as well as tumor growth, without causing significant harm in the mice, the researchers found.
“Our results suggest that inhibiting ATF4 could act against many types of cancer, and we are actively pursuing this strategy,” said the study’s lead author. Constantinos Koumenis, PhD, Richard H. Chamberlain Professor of Oncology Research in Penn’s Department of Radiation Oncology. “Every tumor we looked at upregulates ATF4.”
ATF4 is produced in cells as part of a broad response to stresses such as oxygen or nutrient deprivation. It functions as a master switch for the activities of hundreds of genes that help cells survive these stresses. As the Koumenis lab and others have shown in recent yearsmany types of tumors depend on this ATF4-associated stress response to survive despite the severe stresses they create for themselves by their rapid growth.
The researchers began the new study by designing mice whose ATF4 gene could be deleted from the whole body at any time. They found that if they removed ATF4 before or even after tumors started growing in the mice, tumor growth and their ability to spread to distant organs were greatly impaired. The scientists then used a powerful and relatively new technique called single-cell RNA sequencing to examine the impact of ATF4 deletion in all tumor cell types and observed a surprisingly large effect on a population of cells. supporting cells called cancer-associated cells. fibroblasts (CAF).
Fibroblasts are supporting cells that exist in virtually every organ, producing collagen, a key structural protein, promoting the formation of new blood vessels, and generally aiding in tissue repair and maintenance. Many types of tumors co-opt neighboring fibroblasts, shifting them into CAF mode in which they primarily support the tumor. However, the researchers observed that in their ATF4-deficient mice, CAFs often lacked the usual activation markers and were defective in collagen production and secretion of molecules that promote the growth of new vessels. As a result, levels of collagen and tumor-supplying blood vessels were dramatically reduced in mouse tumors, causing massive tumor cell death.
When the scientists suppressed ATF4 only in the fibroblasts, they saw a tumor-slowing effect almost as strong as that observed with the suppression of ATF4 throughout the body. And when the researchers added normal ATF4-containing fibroblasts to ATF4-deficient mice, the growth-slowing effect of ATF4 deletion was largely reversed.
“These results indicate that ATF4 support for tumors is largely mediated by CAFs,” Verginadis said.
Highlighting the likely relevance of their findings to human cancers, the researchers found that in tumor tissues from human pancreatic cancer and melanoma patients, there was a significant correlation between markers of ATF4 activity and markers of the production of collagen. Additionally, in cases of melanoma, higher collagen production was correlated with worse prognoses.
The researchers hope that targeting ATF4 will not have unacceptable side effects, since mice in which the gene was deleted as adults showed only modest and temporary weight loss and d other minor anomalies.
“Overall, ATF4 appears to be an attractive cancer target,” Koumenis said. “A drug that inhibits it would block its pro-tumor effect not only in tumor cells but also in cancer-associated fibroblasts, so it should be a double whammy for the tumor. But we are still a few years away from that.
Koumenis’ lab is currently working on developing ATF4 inhibitors that could be tested in further animal studies and, ultimately, in human cancer patients.
Reference: Verginadis II, Avgousti H, Monslow J, et al. An integrated stromal stress response activates cancer-associated perivascular fibroblasts to drive angiogenesis and tumor progression. Nat Cell Biol. 2022. do: 10.1038/s41556-022-00918-8
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