A new study has found that molecules that help control gene activity are linked to both the growth of skin cancers and their ability to evade the body’s immune defenses.
Scientists at New York University Langone Health and its Perlmutter Cancer Center have discovered that a key protein known as the transcription factor HOXD13 plays a central role in melanoma. This protein is important in the formation of blood vessels that supply oxygen and nutrients to tumors. Transcription factors such as HOXD13 control how genetic instructions in DNA are translated into proteins that build and maintain the body.
HOXD13 promotes tumor blood supply
This study cancer discoveryshowed 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.
Effect on immune system response
The research team also found that melanoma patients with high HOXD13 levels had fewer cytotoxic T cells in their blood. These immune cells are responsible for identifying and destroying cancer cells. Additionally, patients with elevated HOXD13 activity had a reduced ability of T cells to invade tumors.
“Our study provides new evidence that the transcription factor HOXD13 is a powerful driver of melanoma growth and that it suppresses T cell activity needed to fight the disease,” said study principal investigator Pietro Berrico, Ph.D., a postdoctoral fellow at New York University’s Grossman School of Medicine and Perlmutter Cancer Center.
How tumors create immune barriers
Further analysis revealed that HOXD13 alters the peritumoral environment in a way that dampens the immune response. It increases the level of CD73, which also increases the level of adenosine. This substance acts as a protective barrier for tumors by slowing the invasion of T cells and preventing them from entering cancerous tissue. Turning off HOXD13 allowed more T cells to infiltrate tumors.
“This data supports combined targeting of angiogenesis and adenosine receptor pathways as a promising new treatment for HOXD13-driven melanoma,” said study principal investigator Eva Hernando Monge, Ph.D., professor of pathology at New York University Grossman School of Medicine and member of the Perlmutter Cancer Center.
Possibility of new combination therapy
Hernando-Monge noted that clinical trials are already underway with drugs that block VEGF or adenosine receptors in melanoma and other cancers. Some of these studies have combined these drugs with immunotherapy (drugs that use the immune system to attack cancer).
If these trials yield positive results, the research team will consider a combination of both VEGF and adenosine receptor inhibitors for patients with particularly high HOXD13 levels.
The researchers also plan to examine whether these same pathways can be targeted in other cancers where HOXD13 is elevated, such as certain glioblastomas, sarcomas, and osteosarcomas.
Research details and global collaboration
To reach these conclusions, scientists analyzed tumor samples from more than 200 melanoma patients in the United States, Brazil, and Mexico to determine which biological pathways were more or less active. HOXD13 emerged as an important factor. Additional experiments in mice and human melanoma cell lines confirmed that this protein promotes 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
This research was supported by National Institutes of Health grants P30CA016087, R01CA274100, P50CA225450, and U54CA263001, as well as funding from the Melanoma Research Foundation, Melanoma Research Alliance, UK Medical Research Council grant MR/S01473X/1, and Brazilian National Council for Scientific and Technological Development (CNPQ) grant. 442091/2023-0 and 309661/2023-4, Wellcome Trust Career Development Award 227228/Z/23/Z.
In addition to Hernando-Monge and Berico, contributors from NYU Langone include 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, Markus Schober Contains.
Collaborators from outside institutions include Irving Wilmer and M. Estefania Vázquez-Cruz, in addition to principal investigator Carla Daniela Robles Espinoza of the National Autonomous University of Mexico in Juriquilla. Additional contributors were Mateus Liberio and Annie Squivinato, along with lead researcher Patricia Possic from the Brazilian National Cancer Institute in Rio de Janeiro.
