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Researchers at �ٺ���Ƶ Health’s Perlmutter Cancer Center are developing a better understanding of the molecular mechanisms that drive cancer metastasis, focusing on the role of a recently discovered form of RNA in melanoma metastasis and how nutrient availability and altered metabolism cooperate to promote tumor evolution and metastasis in the brain.

Absence of Circular RNA Promotes Melanoma Progression

While it is known that genetic alterations that affect cellular signaling pathways have been extensively studied in melanoma, they alone are insufficient to explain the metastatic behavior of these tumors. For example, tumors with the same mutations in those pathways can be very aggressive and metastasize rapidly or can have a more indolent course and be cured surgically. Work in the laboratory of , professor in the at �ٺ���Ƶ, is aimed at understanding the mechanisms that lead to melanoma metastasis. Dr. Hernando-Monge and her colleagues are investigating the contribution of so-called noncoding RNAs, such as recently discovered circular RNAs (circRNAs) and long noncoding RNAs (LINC RNAs), as well as the epigenome (how genes are packaged and regulated in the nucleus), in promoting metastatic behavior.

Dr. Hernando-Monge’s lab recently found that the loss of a particular circRNA called CDR1as promotes metastasis in melanoma. CDR1as sequesters IGF2BP3, an RNA-binding protein that controls the stability of messenger RNAs involved in invasion and metastasis. In the absence of CDR1as, IGF2BP3 is released and stabilizes pro-metastatic targets, thereby promoting melanoma progression. Analysis of human melanoma tissues also linked higher CDR1as levels to increased patient survival. This is the first study to expose a circRNA as a suppressor of metastasis.

The study also identified LINC00632, a LINC RNA, as the source of CDR1as in cells. Experiments further revealed that an epigenetic mechanism in melanoma cells—histone methylation—silences the LINC00632 gene, which halts CDR1as production.

“CDR1as silencing could represent a mechanism that helps cells migrate during normal fetal development but drives metastasis when it is turned on in tumors,” Dr. Hernando-Monge says.

Cancer Cells Metastasize by Adapting to the Brain’s Environment

For treating a subset of brain metastases, stereotactic radiosurgery techniques such as Gamma Knife® radiosurgery are highly effective with good outcomes, yet patients inevitably return for follow-up treatments as brain metastases recur. Although there are known genetic drivers of tumors, there are few genes known to specifically enable brain metastases.

Michael E. Pacold, MD, PhD, assistant professor in the at �ٺ���Ƶ, and his colleagues have been exploring what is different about the brain environment that cancer metastases must adapt to in order to survive in the brain.

In a recent collaboration with Lewis Cantley, PhD, at Weill Cornell Medical Center, Dr. Pacold and his colleagues used the brain cerebrospinal fluid as an approximation of available nutrients in the brain environment and determined that the brain microenvironment is low in both serine and glycine, which are crucial for tumor growth. They also found that tumor cells that are effective in colonizing the brain are serine prototrophs, meaning that they have the ability to grow in conditions where serine and glycine concentrations are limited.

Using small molecule inhibitors of serine synthesis in a mouse model of breast cancer brain metastasis, the researchers were able to attenuate and, in some cases, prevent the colonization of the brain by these tumors. They also have preliminary evidence that when melanoma cells are placed in an environment similar to the brain and treated with inhibitors of serine synthesis, they don’t grow.

Dr. Pacold says this study reflects a shift from thinking not only about the behavior of individual tumor cells, but looking at the environments they live in and targeting therapy not just to the tumor cell, but to its metabolic microenvironment.

“Going forward, we’re going to be looking a lot more at cancer cells and the context in which they grow,” Dr. Pacold says. “From the standpoint of drug development, we’re going to have to consider how the cellular environment might alter the efficacy of the drugs themselves.”