A recent study led by researchers at NYU Langone Health and its Perlmutter Cancer Center has identified the transcription factor HOXD13 as a key driver of melanoma growth and immune evasion. The findings were published in the journal Cancer Discovery.
The research showed that HOXD13 is crucial for angiogenesis, which provides tumors with the blood supply necessary for growth. The molecule activates pathways involving vascular endothelial growth factor (VEGF), semaphorin-3A (SEMA3A), and CD73 to promote blood vessel formation. When HOXD13 activity was blocked in experiments, tumor size decreased.
The study also reported that melanoma patients with high HOXD13 activity had lower levels of cytotoxic T cells in their blood compared to those without cancer or with normal HOXD13 levels. Additionally, these T cells were less able to enter tumors in patients with elevated HOXD13.
“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,” said Pietro Berico, PhD, postdoctoral research fellow at NYU Grossman School of Medicine and Perlmutter Cancer Center.
Further analysis revealed that HOXD13 alters the tumor environment by increasing CD73 protein levels, which raises adenosine concentrations. Adenosine impairs T cell function and blocks their entry into tumors. Suppressing HOXD13 led to greater T cell infiltration into tumors during laboratory tests.
“This data supports the combined targeting of angiogenesis and adenosine-receptor pathways as a promising new treatment approach for HOXD13-driven melanoma,” said Eva M. Hernando-Monge, PhD, professor at NYU Grossman School of Medicine and member of the Perlmutter Cancer Center.
Dr. Hernando-Monge noted that clinical trials are ongoing to assess VEGF-receptor and adenosine-receptor inhibitors for melanoma treatment, both separately and in combination with immunotherapies. If successful, her team plans to investigate using both inhibitors together in patients whose melanomas show high levels of HOXD13.
She also plans to explore whether targeting VEGF and adenosine pathways could be effective against other cancers with increased HOXD13 expression, such as certain glioblastomas, sarcomas, and osteosarcomas.
Researchers examined tumor samples from over 200 melanoma patients across the United States, Brazil, and Mexico. Their findings highlighted elevated or suppressed genetic pathways associated with cancer progression. Further testing on mice and human melanoma cells confirmed the role of HOXD13 in promoting angiogenesis and immune system evasion.
Funding for this work came from several sources including grants from the National Institutes of Health; support from organizations like the Melanoma Research Foundation; UK Medical Research Council; Brazilian National Council for Scientific and Technological Development; and Wellcome Trust Career Development Award.
Study contributors included researchers from NYU Langone Health as well as institutions in Mexico (National Autonomous University of Mexico) and Brazil (Brazilian National Cancer Institute).
NYU Langone Health operates a comprehensive health system recognized nationally for patient outcomes by organizations such as Vizient Inc., which ranked it first among academic medical centers nationwide for four consecutive years (https://www.vizientinc.com/). U.S. News & World Report also recently named four NYU Langone clinical specialties best in the country (https://health.usnews.com/best-hospitals/area/ny/nyu-langone-medical-center-6213130). The system includes multiple inpatient locations, an extensive outpatient network across New York state and Florida, two tuition-free medical schools, Perlmutter Cancer Center, and a large research enterprise.
