A molecule that helps control gene activity has now been tied to both the growth of skin cancer and its ability to avoid the body’s immune defenses, according to new research.
Scientists from NYU Langone Health and its Perlmutter Cancer Center found that a key protein, known as the transcription factor HOXD13, plays a central role in melanoma. This protein is critical for the formation of blood vessels that supply tumors with oxygen and nutrients. Transcription factors like HOXD13 regulate how genetic instructions in DNA are turned into proteins that build and maintain the body.
HOXD13 Boosts Tumor Blood Supply
The study, published in Cancer Discovery, showed that HOXD13 activates several biological pathways that increase blood flow to tumors, a process called angiogenesis. These pathways include those involving vascular endothelial growth factor (VEGF), semaphorin-3A (SEMA3A), and CD73. When researchers reduced HOXD13 activity in experiments, tumors became smaller.
Impact on Immune System Response
The team also discovered that melanoma patients with high levels of HOXD13 had fewer cytotoxic T cells in their blood. These immune cells are responsible for identifying and destroying cancer cells. In addition, T cells were less able to enter tumors in patients with elevated HOXD13 activity.
“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 study lead investigator Pietro Berico, PhD, a postdoctoral research fellow at the NYU Grossman School of Medicine and its Perlmutter Cancer Center.
How Tumors Create an Immune Barrier
Further analysis revealed that HOXD13 alters the environment around tumors in a way that weakens immune responses. It increases levels of CD73, which in turn raises levels of adenosine. This substance acts as a protective barrier for tumors by slowing down T cells and preventing them from entering cancerous tissue. When HOXD13 was turned off, more T cells were able to infiltrate tumors.
“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.
Potential for New Combination Treatments
Hernando-Monge noted that clinical trials are already testing drugs that block VEGF receptors or adenosine receptors in melanoma and other cancers. Some of these studies are combining these drugs with immunotherapy (drugs that harness the immune system to attack cancer.)
If these trials show positive results, the research team plans to explore treatments that combine both VEGF and adenosine-receptor inhibitors specifically for patients with high HOXD13 levels.
The researchers also intend to examine whether these same pathways could be targeted in other cancers where HOXD13 is elevated, such as certain glioblastomas, sarcomas, and osteosarcomas.
Study Details and Global Collaboration
To reach these conclusions, the scientists analyzed tumor samples from more than 200 melanoma patients in the U.S., Brazil, and Mexico, identifying which biological pathways were more or less active. HOXD13 emerged as a key factor. Additional experiments in mice and human melanoma cell lines confirmed that this protein drives both blood vessel growth and immune system evasion. Blocking HOXD13, VEGF, and adenosine pathways further demonstrated its importance for tumor survival.
Funding and Research Team
The study was supported by National Institutes of Health grants P30CA016087, R01CA274100, P50CA225450, and U54CA263001, along with funding from the Melanoma Research Foundation, the Melanoma Research Alliance, United Kingdom Medical Research Council grant MR/S01473X/1, Brazilian National Council for Scientific and Technological Development (CNPQ) grants 442091/2023-0 and 309661/2023-4, and the Wellcome Trust Career Development Award 227228/Z/23/Z.
In addition to Hernando-Monge and Berico, contributors from NYU Langone included Amanda Flores Yanke, Fatemeh Vand Rajabpour, Catherine Do, Ines Delclaux, Tara Muijlwijk, Robert Stagnitta, Theodore Sakellaropoulos, Michelle Krogsgaard, Ata Moshiri, Iman Osman, Jane Skok, Amanda Lund, and Markus Schober.
Collaborators from outside institutions included Irving Wilmer and M. Estefania Vazquez-Cruz, along with principal investigator Carla Daniela Robles-Espinoza at the National Autonomous University of Mexico in Juriquilla. Additional contributors were Matheus Riberio and Annie Squiavinato, with principal investigator Patricia Possik at the Brazilian National Cancer Institute in Rio de Janeiro.
