Dartmouth Investigators Identify Mechanism that Drives Melanoma to Metastasize

"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.

Brinckerhoff is the former Nathan Smith Professor of Medicine and of Biochemistry, and past Associate Dean for Science Education at Geisel School of Medicine at Dartmouth, where Mullins is Assistant Professor of Microbiology & Immunology. Their work in cancer is facilitated by Dartmouth's Norris Cotton Cancer Center where Brinckerhoff is a member of the Cancer Mechanisms Research Program and Mullins belongs to the Immunology & Cancer Immunotherapy Research Program.

"CXCR3 signaling in BRAFWT melanoma increases IL-8 expression and tumorigenicity," was supported by grants USPHS T32 Cancer Center Training Grant CA009658 and Immunology Training Grant AI007363, USPHS RO1 CA77267 and RO1 CA134799, and the Hitchcock Foundation Pilot Studies Award.

About Dartmouth-Hitchcock Norris Cotton Cancer CenterNorris Cotton Cancer Center combines advanced cancer research at Dartmouth and the Geisel School of Medicine with patient-centered cancer care provided at Dartmouth-Hitchcock Medical Center in Lebanon, NH, at Dartmouth-Hitchcock regional locations in Manchester, Nashua, and Keene, NH, and St. Johnsbury, VT, and at 12 partner hospitals throughout New Hampshire and Vermont. It is one of 41 centers nationwide to earn the National Cancer Institute's "Comprehensive Cancer Center" designation. Learn more about Norris Cotton Cancer Center research, programs, and clinical trials online at cancer.dartmouth.edu.