Researchers at NYU Langone Health have identified a protein that operates as a dual threat in melanoma, simultaneously fueling tumor growth and cloaking cancer cells from the body's natural defenses. The discovery, published in Cancer Discovery, reveals how a single molecular switch controls both processes and suggests a new path for combination therapies.
The protein in question is HOXD13, a transcription factor that regulates how DNA instructions translate into the proteins that build and maintain cells. In melanoma, HOXD13 activates multiple biological pathways that work in concert to help tumors thrive.
When researchers reduced HOXD13 activity in laboratory experiments, tumors shrank. The protein drives angiogenesis, the formation of blood vessels that deliver oxygen and nutrients to growing tumors. It activates pathways tied to vascular endothelial growth factor, or VEGF, semaphorin-3A, and CD73, all critical to building the tumor's blood supply.
But HOXD13's role extends beyond feeding tumors. The team discovered it also cripples immune surveillance. Melanoma patients with high HOXD13 levels had fewer cytotoxic T cells circulating in their blood and those that existed struggled to penetrate tumor tissue.
The mechanism proved ingenious. HOXD13 elevates CD73, which in turn boosts adenosine levels around the tumor. This chemical acts as a blockade, slowing immune cells and preventing them from entering cancer tissue. When researchers disabled HOXD13, more T cells infiltrated tumors, breaking through the immune barrier.
The study analyzed tumor samples from over 200 melanoma patients across the United States, Brazil, and Mexico, mapping which biological pathways operated at elevated levels. HOXD13 emerged as the critical node. Mouse studies and human cell line experiments confirmed that blocking the protein, along with VEGF and adenosine pathways, significantly impaired tumor survival.
Eva Hernando-Monge, the study's senior investigator and a pathology professor at NYU Grossman School of Medicine, noted that clinical trials are already testing drugs targeting VEGF and adenosine receptors, with some combining them with immunotherapy drugs that mobilize the immune system against cancer. The research team plans to explore whether combining VEGF and adenosine-receptor inhibitors specifically for patients with high HOXD13 could offer better outcomes.
Beyond melanoma, HOXD13 elevation has been detected in other aggressive cancers, including certain glioblastomas, sarcomas, and osteosarcomas. Researchers intend to investigate whether the same pathways could be leveraged across these tumor types.
Author Jessica Williams: "This is the kind of specific molecular target that transforms treatment strategy, turning a dual liability into a dual opportunity for attack."
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