Oct. 6 (UPI) -- Researchers at the Sanford Burnham Prebys Medical Discovery Institute, or SBP, and the University of California San Diego report in a new study that the p62 pathway in tumor stroma could be a potential anti-cancer target.
The study, published Thursday in Cell Metabolism, reveals that a p62 protein deficiency helps tumors and stroma -- supportive tissue surrounding the tumor -- to survive and grow even when being deprived of glutamine, an essential amino acid.
"Cancer has traditionally been treated with chemotherapies that target oncogene addictions -- the oncogenic signals that tumors use to survive," Maria Diaz-Meco, a professor at SBP's NCI-designated Cancer Center, said in a press release.
"We are looking at the non-oncogenic addictions, which are the function of non-mutated genes that also contribute to the survival of many cancers. For example, the stroma is not the cancer, but it's a major component that supports the tumor. We believe that targeting metabolism, not only in mutated tumor cells but also in the stroma, will be a way to find new therapies, regardless of the cancer's mutations."
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For tumors to survive, they have to ensure access to adequate nutrient supplies by rewiring surrounding tissue such as cancer-associated fibroblasts in the stroma.
"What happens when there's nutrient stress?" Diaz-Meco said. "The cancer doesn't have supplies. In its more aggressive forms, nutrient accessibility inside the tumor becomes limited. The tumor eliminates p62 from the stroma to make the stroma more aggressive, more inflammatory and to be able to support the disease."
Researchers found that reducing p62 increased ATF4, an essential transcription factor protein that teaches cells to adapt to situations where nutrients are of short supply in the tumor microenvironment. In their experiments, researchers found ATF4 levels only changed in the stroma, and remained constant in epithelial cells despite p62 levels.
Losing p62 and gaining ATF4 activates a complex pathway that generates the amino acid asparagine, allowing stromal cells and tumor cells to survive and grow regardless of nutrient-poor conditions.
"This offers new strategies to take advantage of the tumor's vulnerabilities," Diaz-Meco said. "We hope that targeting non-oncogenic addictions will generate less resistance, because the stroma is more genetically stable and does not mutate as tumor cells do during aggressive therapies."
