Investigators identify an eye cancer culprit

An illustration showing two different cell subtypes within individual tumors; an indolent subclone with spindle morphology (blue) and an aggressive one with round ‘epithelioid’ morphology (red). (Illustration courtesy of Mathieu Bakhoum, MD, PhD)

Researchers have identified a molecular mechanism that drives the progression of uveal melanoma (UM), an often lethal eye cancer in adults.

The study’s results were published in the journal Nature Communications¹ and might offer an opportunity to develop treatments for earlier suppression of a lethal type of tumor that spreads to other parts of the body.

According to investigators, the study also represents a touchstone in understanding cancer biology, linking two key components of cancer — chromosomal instability (errors in chromosome segregation during cell division) and epigenetic alterations (changes in gene regulation) — that interact to advance disease progression.

The investigators noted that UMs form within eye tissue, often in older adults and people with fair skin. There are an estimated 2500 cases of UM every year in the United States.

The most common therapies for UM are surgery and radiation. However, once UM spreads to other organs, chances of survival are small.

“Up to half of UM patients are prone to developing liver metastasis, which is usually lethal,” Mathieu Bakhoum, MD, PhD, an assistant professor of ophthalmology at the Yale School of Medicine and co-first author of the study, said in a news release. “The reasons why only a group of patients with certain tumor characteristics develop metastasis, and the mechanisms driving metastasis, are unknown, yet crucial to developing target therapies to this lethal disease.”

The research team integrated a variety of genetic and other analyses at the single-cell level to demonstrate that UM progression is propelled by the loss of Polycomb Repressive Complex 1 — proteins that regulate gene expression.

According to the team, this loss leads to aberrant gene expression and errors in the way chromosomes segregate during cell division.

Eventually, this leads to an inflammatory response that makes the tumor more aggressive.

“By uncovering key steps involved in tumor progression, our work highlights an opportunity for earlier therapeutic intervention to suppress tumor evolution,” Bakhoum said in the release.

In addition to Bakhoum, the principal investigators on the study include Ashley Laughney, PhD, from Weill Cornell Medical School, Samuel Bakhoum, MD, PhD, from Memorial Sloan Kettering Cancer Center, and Paul Mischel, MD, from Stanford University. Jasmine Francis, MD, from Memorial Sloan Kettering is co-first author.

The research was supported by the Melanoma Research Alliance, the Burroughs Wellcome Fund, the Fund for Ophthalmic Knowledge, and the National Cancer Institute.

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Reference

1. Bakhoum, M.F., Francis, J.H., Agustinus, A. et al. Loss of polycomb repressive complex 1 activity and chromosomal instability drive uveal melanoma progression.Nat Commun 12, 5402 (2021). https://doi.org/10.1038/s41467-021-25529-z