A gene signature for ribosomal protein large/small subunits (RPL/RPS) has been linked to circulating tumor cells (CTCs) that cause brain metastasis in melanoma, the most aggressive and lethal skin cancer. Brain metastases are a common and devastating effect of this type of malignancy, although it also spreads to other organs, such as the lungs and liver.
Besides shedding light on how this cancer spreads to the brain, this finding, from University of New Mexico Health Sciences Center, could lead to better understanding of metastasis in general, and offer new targets for drugs that could slow or halt this process, first author Dario Marchetti told Inside Precision Medicine. One report says that over 10% to 26% of all patients who die from their cancer will develop brain metastases.
“Brain metastases are increasing,” Marchetti pointed out. “As tumor cells become resistant to therapy, they are more common. They come back and colonize the organs.”
The group studied samples from:
- Melanoma patients with metastases, but not in the brain
- Melanoma patients with metastases, including in the brain
- Melanoma patients with brain metastases who had taken a checkpoint inhibitor for several months
- A preclinical mouse model in which CTCs were injected and were later tested by MRI to evaluate temporal and spatial spread in the brain
Brain metastases are unique both because of their microenvironment and because of the blood brain barrier. These researchers were interested in which CTCs can penetrate that barrier, grow, then perhaps spread further, and how they accomplish that. Only a fraction of CTCs can reach the brain.
“Our hypothesis was to define the characteristics of CTCs that cause brain metastases in melanoma patients, without presuppositions, and how they become the seeds of metastasis,” said Marchetti.
The group did transcriptional profiling on these melanoma-related samples. All of their analyses pointed to an RLP/RPS gene signature associated with brain metastasis. RPLs are 60 subunits or larger, while RPSs are 40S or smaller. (The subunits in between comprise the ribosomal particle that initiates and regulates translation).
“We were very surprised by this,” Marchetti said.
But the team made sense of it.
Notably, 26 of the 33 gene pathways related to the signature were all involved in translational processes. This points to gene expression regulation as a key player in melanoma brain metastasis.
“Once we performed pathway analysis, we found that the translational machinery was highly upregulated,” Marchetti added.
In addition, another group of researchers had much earlier found that, in animal studies, 19 pathways of the signature were related to breast cancer metastasis (Nature, 2009). This suggests the signature may work across cancers.
Further, the Marchetti teams’ new mouse model of brain metastasis is an improvement over alternatives, he noted. For one thing, they saw metastases develop in these mice as early as 24 hours after injection and the researchers could detect hundreds of brain metastases nodules in these mice in a short time.
Ultimately, Marchetti said he would like to collaborate with pharma companies to find new drugs to address the targets uncovered in this signature. He points out that there are only two drugs that currently target just two members of the RP/RPS signature they have identified. No approved drug targets any of these.
The team therefore think there is a unique opportunity for novel drug discovery against this signature to halt CTC spread during it’s “vulnerability window.”
“This identification of a well-demarcated subset of melanoma CTCs raises the possibility of pharmacological targeting of metastasis-competent CTCs, notably those to the brain,” Marchetti said.