A newly identified molecular mechanism is driving both the growth of melanoma and the cancer’s ability to evade the body’s immune defenses, according to research published in Cancer Discovery on . The study, led by researchers at NYU Langone Health and its Perlmutter Cancer Center, centers on the transcription factor HOXD13 and its surprisingly central role in melanoma progression.
Transcription factors, like HOXD13, are crucial regulators of gene activity. They control the rate at which DNA’s instructions are used to build proteins, the workhorses of cellular structure and function. This research demonstrates that HOXD13 isn’t just involved in normal developmental processes – it’s actively hijacked by melanoma cells to fuel their growth and survival.
The researchers found that HOXD13 is essential for angiogenesis, the formation of new blood vessels. Melanoma tumors require a robust blood supply to deliver oxygen and nutrients, and HOXD13 appears to be a key driver of this process. Specifically, the study showed that HOXD13 spurs activity in signaling pathways involving vascular endothelial growth factor (VEGF), semaphorin-3A (SEMA3A), and CD73 – all known to promote blood vessel growth. Experiments where HOXD13 activity was suppressed resulted in measurable tumor shrinkage, indicating its critical role.
However, the impact of HOXD13 extends beyond simply providing nutrients to the tumor. The study also revealed a significant connection between HOXD13 activity and immune evasion. Researchers observed lower levels of cytotoxic T cells – the immune system’s primary cancer killers – in melanoma patients with high HOXD13 activity. The ability of these T cells to even *reach* the tumor was diminished in patients with elevated HOXD13 levels.
“Our study provides new evidence that transcription factor HOXD13 is a potent driver of melanoma growth and that it suppresses the T cell activity needed to fight the disease,”
Pietro Berico, PhD, study lead investigator, postdoctoral research fellow, NYU Grossman School of Medicine and its Perlmutter Cancer Center
The mechanism behind this immune suppression involves altering the tumor microenvironment. HOXD13 boosts levels of the protein CD73, which in turn increases levels of adenosine. Adenosine acts as a shield for the tumor, effectively putting the brakes on T cells and preventing them from infiltrating the tumor mass. When researchers deactivated HOXD13, they observed a corresponding increase in T cell infiltration, suggesting a direct link between the transcription factor and immune cell access.
This dual role – promoting angiogenesis and suppressing the immune response – makes HOXD13 a particularly attractive therapeutic target. The researchers suggest that combining therapies targeting angiogenesis with those that counteract adenosine signaling could be a promising new approach to treating HOXD13-driven melanoma. “This data supports the combined targeting of angiogenesis and adenosine-receptor pathways as a promising new treatment approach for HOXD13-driven melanoma,” said study senior investigator Eva Hernando-Monge, PhD, a professor in the Department of Pathology at the NYU Grossman School of Medicine and a member of the Perlmutter Cancer Center.
Importantly, clinical trials are already underway evaluating the safety and efficacy of both VEGF-receptor and adenosine-receptor inhibitor medications for melanoma and other cancers. Some of these trials are even combining these inhibitors with existing immunotherapies, which aim to harness the power of the immune system to fight cancer. The NYU Langone team plans to initiate clinical investigations specifically targeting melanoma patients whose tumors exhibit elevated HOXD13 levels with a combination of VEGF and adenosine-receptor inhibitors if the current trials prove successful.
The scope of this research may extend beyond melanoma. Hernando-Monge’s team intends to investigate whether VEGF and adenosine pathways are also potential targets in other cancers where increased HOXD13 is present, including glioblastomas, sarcomas, and osteosarcomas. This suggests that the findings could have broader implications for cancer treatment.
The study involved a comprehensive analysis of tumors from over 200 melanoma patients across the United States, Brazil, and Mexico. This analysis identified HOXD13 as a key player in the signaling pathways that were either elevated or suppressed in these tumors. Further experiments, conducted in mice and human melanoma cell lines, confirmed that HOXD13 drives the angiogenesis and immune evasion pathways. Tests involving the inhibition of HOXD13, VEGF, and adenosine then solidified the conclusion that HOXD13 is central to the cancer’s growth and survival.
The research was funded by grants from the National Institutes of Health, the Melanoma Research Foundation, the Melanoma Research Alliance, and several international funding bodies, including the United Kingdom Medical Research Council and Brazilian National Council for Scientific and Technological Development.