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, published in Cancer Discovery, show that HOXD13 is essential for the development of blood vessels that supply tumors with oxygen and nutrients.
The research team discovered that HOXD13 increases activity in pathways related to angiogenesis, including those involving vascular endothelial growth factor (VEGF), semaphorin-3A (SEMA3A), and CD73. Suppressing HOXD13 activity in experimental models resulted in tumor shrinkage.
In addition, the study found lower levels of cytotoxic T cells—the immune cells responsible for attacking cancer—in melanoma patients with high HOXD13 activity compared to those without the cancer or elevated HOXD13. These patients also showed reduced T cell infiltration into tumors.
“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, lead investigator and postdoctoral research fellow at NYU Grossman School of Medicine and Perlmutter Cancer Center.
The authors also observed that HOXD13 alters the tumor environment by increasing levels of CD73, which raises adenosine production. Adenosine acts as a shield for tumors by limiting T cell entry. When HOXD13 was inhibited, there was an increase in T cell presence within tumors.
“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, senior investigator and professor at NYU Grossman School of Medicine’s Department of Pathology.
Dr. Hernando-Monge noted ongoing clinical trials are assessing VEGF-receptor and adenosine-receptor inhibitors—sometimes in combination with immunotherapies—for melanoma and other cancers. If these approaches prove effective, future studies may explore their use specifically in patients with elevated HOXD13 levels.
The research team plans further investigation into whether these pathways could be targeted in other cancers where increased HOXD13 is present, such as glioblastomas, sarcomas, and osteosarcomas.
For this study, over 200 melanoma patient tumor samples from the United States, Brazil, and Mexico were analyzed to identify active or suppressed pathways. Further experiments using mice and human melanoma cell lines confirmed the role of HOXD13 in promoting angiogenesis and immune evasion. Inhibiting HOXD13 alongside VEGF or adenosine confirmed its importance for cancer growth.
Funding for this work came from several sources including National Institutes of Health grants P30CA016087, R01CA274100, P50CA225450, U54CA263001; Melanoma Research Foundation; Melanoma Research Alliance; UK Medical Research Council grant MR/S01473X/1; Brazilian National Council for Scientific and Technological Development grants 442091/2023-0 and 309661/2023-4; Wellcome Trust Career Development Award 227228/Z/23/Z.
Researchers from NYU Langone involved include Amanda Flores Yanke; Fatemeh Vand Rajabpour; Catherine Do; Ines Delclaux; Tara Muijlwijk; Robert Stagnitta; Theodore Sakellaropoulos; Michelle Krogsgaard, PhD; Ata Moshiri, MD MPH; Iman Osman MD; Jane Skok PhD; Amanda W. Lund PhD; Markus Schober PhD. Additional contributors are from National Autonomous University of Mexico (Irving Wilmer, M. Estefania Vazquez-Cruz, Carla Daniela Robles-Espinoza) and Brazilian National Cancer Institute (Matheus Riberio, Annie Squiavinato, Patricia Possik).
NYU Langone Health is recognized nationally for its patient outcomes across multiple locations including seven inpatient sites and more than 320 outpatient centers. It has been ranked No. 1 among academic medical centers by Vizient Inc., with four clinical specialties recently rated best nationwide by U.S. News & World Report.
