In a unique partnership demonstrating excellence in “team science,” Dartmouth investigators from Norris Cotton Cancer Center identified a role for the molecule CXCR3 (widely known to regulate the migration of immune cells) as a key mediator of melanoma metastasis. The paper, “CXCR3 signaling in BRAFWT melanoma increases IL-8 expression and tumorigenicity,” by Molly H. Jenkins, PhD, Constance E. Brinckerhoff, PhD and David W. Mullins, PhD is published in PLOS One.
“We hypothesized that a melanoma may be able to sense that its environments is becoming inhospitable, and then respond by activating 'escape mechanisms' to leave the environment in search of greener pastures,” explained Mullins. “We demonstrate that melanomas up-regulate the chemokine receptor CXCR3 in response to stress, including nutrient or oxygen deprivation, then use CXCR3 to launch migratory processes. Understanding this mechanism may lead to therapies to interfere with cancer metastasis and could help improve the efficacy of conventional or immune-based therapies.”
The Brinckerhoff lab studied the processes by which tumor cells detach themselves from their primary site as they invade their local environment and metastasize to distant sites. Meanwhile, the Mullins lab focused on the molecule that immune cells use to migrate into tissues. Together, they addressed the role of one specific molecule, CXCR3, known to be a critical mediator of immune cell migration, and identified a mechanism by which CXCR3 directs and facilitates metastasis of melanoma.
Metastasis, which is movement of a tumor from its original location to other organs, is a major problem for patients with cancer. The vast majority of deaths from cancer are due to metastatic tumor growth because these tumors are often resistant to standard therapy and inaccessible to surgery.
To date, most research on melanoma has focused on just half of the melanomas that have a particular mutation. The Brinckerhoff and Mullins collaboration took on the other half of melanomas that don't have the same mutation but still have a history of invading other organs and metastasizing. The significance of this work is its descriptions of alternative mechanisms by which tumors move and settle in new locations.
The Brinckerhoff and Mullins team used Dartmouth's Shared Resources to accomplish their study, including the DartLab Flow Cytometry Core to do flow analyses and the Transgenic and Genetic Construct Mouse Resource Service for specialized mice. All 14 of Dartmouth's Shared Resources are open to outside investigators by arrangement.
“Knowing that melanomas use CXCR3 to induce the metastatic program may allow specific pharmacologic or immunologic targeting, leading to potential interventions to reduce or prevent metastasis,” said Brinckerhoff.
Looking forward, the team will continue to study the mechanisms that regulate CXCR3 expression in melanoma, in order to understand how environmental or immunologic stress may induce its expression.
Source: Norris Cotton Cancer Center