Cells from cancerous tumors can spread, or metastasize, throughout the body. Researchers have long sought to understand what determines where those cells will go and thrive in order to more effectively treat the cancer and prevent metastasis.
Researchers at Yale School of Medicine (YSM) have now identified biological markers for a rare, aggressive eye cancer that predict the likelihood of secondary tumors forming in the liver. The finding, published recently in npj Precision Oncology, offers new opportunities for both monitoring the cancer’s progression in patients and evaluating how well drugs might treat it.
“We found genetic evidence that organotropism the non-random pattern of metastasis to particular organs in the body is wired even before the tumor has metastasized.”Mathieu Bakhoum, MD, PhD, Assistant Professor of Ophthalmology and Visual Science at YSM
“Our paper shows the genetic predisposition that explains a cancer’s metastatic preference for certain organs,” Mathieu Bakhoum, MD, PhD, assistant professor of ophthalmology and visual science at YSM and senior author of the study.
Predicting where uveal melanoma will spread
For more than a century, researchers have thought about the spread of cancer through the lens of the “seed and soil” hypothesis. When cancerous cells break from the primary tumor (the seed), they can travel through the body. Secondary tumors can only grow in a supportive environment (the soil). So, what makes another organ favorable to traveling cancer cells?
The eye cancer uveal melanoma is an ideal candidate to explore the mechanisms behind this long-held theory, as it has a strong metastatic preference for the liver.
“For 90% of patients, when uveal melanoma metastasizes, it will involve the liver,” says Bakhoum. “People have asked why the liver—is it circulation, anatomy, biology?”
Previously, Bakhoum and his team identified two genetically distinct uveal melanoma subclones within primary tumors; subclones are different cell populations within a tumor that have their own particular genetic characteristics. In this study, the researchers set out to determine whether those subclones follow different metastatic routes.
They analyzed whole exome and genome sequencing on 144 metastatic uveal melanoma samples obtained from published data and from the Specimen Resource Core of the Yale SPORE in Skin Cancer. The team then compared key genetic mutations within metastases that developed in the liver with metastases that developed in other organs.
“We wanted to identify genetic patterns that might explain why the liver is so frequently involved in metastasis,” says Bakhoum.
The researchers found that while both clones could move to other organs at equal rates, liver metastases were dominated by clones with a mutation in a gene called BAP1. The results imply that the metastatic destination is not random; it is shaped early by the genetic identity of the tumor clone, with certain clones better equipped to survive and expand in the liver microenvironment.
Bakhoum and his team are now studying why cells with the BAP1 mutation preferentially grow in the liver.
The findings of this new study could help improve patient care. For instance, clinicians that detect high-risk molecular features in a patient’s primary tumor may be able to tailor surveillance, such as closer monitoring for liver metastasis, and improve how patients are stratified for clinical trials.
These findings could also inform how to evaluate the results from ongoing clinical trials of new drug treatments for uveal melanoma. According to Bakhoum, both tumor genetics and site of metastasis should be considered when interpreting trial results, rather than treating all patients as a single, uniform group.
“Each group could potentially respond to drugs differently,” he says. “We need to consider both the genetics of the tumor and the site of metastasis when analyzing drug outcomes.”
Stratifying (or at least analyzing outcomes) by molecular subtype and metastatic pattern could reveal differences in response and survival patterns. Bakhoum also notes that data from completed trials could be reanalyzed through this framework to determine whether certain therapies performed better in patients with different tumor clones and metastatic patterns.
“The concept of organotropism is very exciting,” he says. “This is one of the first studies to provide genetic evidence that metastatic patterns in uveal melanoma are not random, and that distinct tumor clones are associated with specific organ sites.”
(Newswise/HG)