For those living with advanced melanoma, brain metastases— malignant growths that occur when cancer cells travel to the brain—are particularly challenging to treat. New findings, published April 18 in Cellular and Molecular Life Sciences, could help clinicians improve treatments for this form of late-stage cancer and reduce the risk of recurrence.
Brain metastases are a risk from any cancer but are especially prevalent in certain types, including melanoma. Researchers estimate as many as 40% to 60% of those with late-stage melanoma will develop brain metastases, often resulting in death. In some cases, cancer growth is supported by a process known as vascular mimicry, in which tumors form their own vasculature, allowing nutrient flow to the tumor. Now, a team of researchers has investigated the underlying mechanisms of vascular mimicry to better understand how this process may drive the outgrowth of melanoma brain metastases and their poor response to current cancer treatments. The researchers also hope to discover how inhibiting this process could lead to a potential novel therapy.
“Brain metastasis patients are often excluded from clinical trials [due to concerns regarding drug penetration, toxicity, and their historically poor prognosis], which has slowed the development of systemic therapies for these patients,” says Lucia Jilaveanu, MD, PhD, associate professor of medicine (medical oncology), member of Yale Cancer Center, and the study’s principal investigator. “Our team is hoping to provide proof-of principle of the therapeutic value of inhibiting vascular mimicry as a strategy for treating melanoma brain metastases.”
Do angiogenesis and vascular mimicry cause tumor growth?
Cancers, including melanoma, can remain dormant in the body for long periods of time. This dormancy is often followed by an aggressive outbreak in which the melanoma rapidly spreads and is difficult to control with existing therapies.
Scientists have long believed that the reactivation of dormant cancers can be triggered by a process known as angiogenesis (the development of new blood vessels). Each of our organs has a local vasculature system; through angiogenesis, tumors stimulate existing nearby blood vessels to create new vessels which facilitate the tumors’ growth.
There is emerging evidence that the cancer reactivation may also be triggered by vascular mimicry. Through this process, cancer stem cells differentiate into cells that mimic vascular endothelial cells—the cells that line blood vessels. These cells form tubular structures that connect to our normal vasculature, allowing for the active circulation of blood within the tumor.
Jilaveanu has been focusing on the biology of brain metastasis for more than a decade. Part of her research includes the development of mouse models to help her team better understand how to treat the disease. One of the models developed in her lab replicated the transition from dormant micro-metastasis to macro-metastasis. Through this work, they uncovered a link between brain metastasis and several previously undiscovered molecules. This inspired further studies, which found that these molecules were linked to the regulation of vascular mimicry.
How does vascular mimicry drive melanoma brain metastasis?
In their latest investigation on the mechanisms of vascular mimicry in melanoma brain metastasis, the team integrated several approaches. First, they analyzed tumor tissues from both on and outside the brains of patients who had undergone surgery for melanoma. They found an increased density of vascular mimicry in brain metastases compared to tissue collected from other kinds of tumors. Furthermore, they uncovered a positive correlation between vascular mimicry density and tumor volume, as well as cerebral edema [brain swelling].
Next, they cultured human melanoma cell lines taken from tumors of the brain and from other anatomical sites of patients treated at Yale New Haven Hospital, as well as mouse melanoma cell lines. Once again, they found that cells taken from brain metastases had developed structures of vascular mimicry, whereas cells of tumors from outside the brain had not. This evidence suggests that brain metastases are more likely than tumors outside the brain to utilize vascular mimicry over angiogenesis.
Are YAP/TAZ inhibitors a potential treatment for melanoma brain metastasis?
Through previous work in her lab, Jilaveanu and her team have pinpointed a signaling pathway, known as YAP/TAZ, that is involved with the regulation of vascular mimicry. “YAP and TAZ are two transcription cofactors [proteins involved in the transcription of genetic information] that are widely expressed in melanoma and involved in melanoma progression,” she says.
In their current study, the researchers studied the effects of applying drugs that target YAP/TAZ on the vascular mimicry in their models. They applied verteporfin, a macular degeneration drug that treats the abnormal blood vessel growth, and CA3, another YAP/TAZ inhibitor, to their brain metastatic cell lines. They also used TED347, a newer drug that is more specific and better tolerated. They found that the drugs inhibited vascular mimicry and reduced cancer cell growth.
Furthermore, the team employed their previously developed mouse models of metastatic melanoma to study the disease in vivo. Treated mice lived longer than the controls, the researchers found. “Vascular mimicry can be specifically targeted, and this impacts metastatic growth,” says Jilaveanu.
Some current therapies for treating malignant tumors target mechanisms underlying angiogenesis. Thus, tumors that preferentially utilize vascular mimicry may be resistant to these treatments. Jilaveanu hopes that her work will show clinicians the potential therapeutic value of inhibiting both angiogenesis and vascular mimicry when treating melanoma. “Brain metastases pose a major challenge in the clinic due to a lack of effective therapy,” she says. “Focusing on vascular mimicry as a mechanism of treatment resistance will be very significant for our patients.”