The Atypical Chemokine Receptor-1 (ACKR1) protein, also known as the Duffy Antigen, controls patterns of signal proteins called chemokines that can be hijacked by cancer cells and lead to metastasis and tumor proliferation. Existing research suggests expression of ACKR1 can limit cancer aggressiveness and invasiveness, but these mechanisms have yet to be defined. In a new Frontiers review, MCW cancer researchers further explored the patterns of ACKR1, chemokines, and other molecules that interact with ACKR1 to gain new insights on effective ways to target cancer and other diseases.
“We identified ACKR1 as a master regulator of over 20 chemokine ligands that is involved in three major aspects of cancer: tumor growth, directed migration to vulnerable sites, and effective immune responses,” said Kyler Crawford, PhD, a recent graduate from the Volkman Lab and author of the study. “Additionally, we described how the ‘Duffy-negative’ clinical polymorphism is a significant genetic change that limits ACKR1 expression in people with West African ancestry and is an underappreciated determinant of disparate cancer outcomes.”
Dr. Crawford found the ancestral genetic change to be present in the majority of people in Africa, most African-Americans, and in populations across the Arabian Peninsula. While the Duffy-negative polymorphism is an adaptation that provides immunity to the Plasmodium vivax malaria pathogen, it leads to a condition called Duffy-associated neutropenia and a variant ACKR1 protein, ACKR1-FyB. “This makes receiving chemotherapy more difficult and increases levels of circulating chemokines that may contribute to cancer progression. Testing for ACKR1 phenotype and expression in tumor biopsies may be a clinically useful cancer biomarker,” he said.
“Cancer patients with Duffy-negative status are at increased risk of chemokine-mediated cancer progression, and the connection to West African ancestry links this biological determinant with other sources of disparity contributing to worse cancer outcomes,” he added.
Results of Dr. Crawford’s research, which was supported by MCW’s Medical Scientist Training Program, inspired him and Dr. Volkman to further investigate the structural changes in the FyB variant and its impact on the regulatory functions of ACKR1. They hope this work improves awareness of the role of ACKR1 in patient physiology and helps contribute to the development of precision-medicine therapies that target the chemokine network.
Read the full study in Frontiers.