Roswell Park Scientists Identify Novel Tumor Properties That Drive Metastatic Breast Cancer

BUFFALO, N.Y. — Metastasis, or the spread of cancer cells from a primary tumor to distant organs, lacks effective treatment options and remains a major cause of cancer-related deaths. To better understand how metastasis works — and how it might be controlled — scientists at Roswell Park Comprehensive Cancer Center have zeroed in on the role of the metabolic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 (PFKFB4) in the spread of triple-negative breast cancer (TNBC). Their study, “Hypoxic activation of PFKFB4 in breast tumor microenvironment shapes metabolic and cellular plasticity to accentuate metastatic competence,” appears today in Cell Reports.

Dr. Subhamoy Dasgupta

Cancer cells need oxygen to proliferate and spread, and hypoxia — a decreased level of oxygen — is just one challenge to their survival in the tumor microenvironment (TME). The Roswell Park team, led by Subhamoy Dasgupta, PhD, Associate Professor of Oncology in the Department of Cell Stress Biology, has discovered how cancer cells are able to transform within the primary tumor in spite of that stress and to become capable of metastasizing to distant organs.

“One of the critical challenges is to find out why some patients develop metastatic breast cancer and others don’t,” says first author Tao Dai, PhD candidate in tumor immunology at Roswell Park. Using data from The Cancer Genome Atlas and Gene Expression Omnibus, the research team looked for subtypes of breast cancer that were closely associated with both elevated expression of PFKFB4 and poor prognosis. Although PFKFB4 was highly expressed in patients with either TNBC or hormone-positive breast cancer, it was prognostic of poor survival only in TNBC patients. The team also found that expression of PFKFB4 was higher in metastatic breast cancer lesions in the lung, brain and liver than in the primary tumors from which they originated, indicating that PFKFB4 tumors could be especially aggressive and invasive.

Further, the study showed that in hypoxic tumors, PFKFB4 is essential to the survival of TNBC cells, because it enables those cells to adapt metabolically to stressors presented by the TME.

To test this possibility, Dr. Dasgupta and his colleagues worked with two groups of mouse models of highly metastatic triple-negative breast cancer (TNBC) — one genetically modified to inhibit PFKFB4 and the other unmodified, to serve as a control group. Following tumor engraftment, the researchers surgically resected the primary tumors in both groups and monitored the mice for tumor recurrence to determine the ability of PFKFB4 to promote metastasis in the absence of the primary tumor. The group in which PFKFB4 was inhibited showed a significant reduction in metastatic lesions, while the control group “showed profound distant organ metastasis within five weeks of primary tumor removal.”

The first signs of metastasis, found mostly in the axillary lymph nodes, were detected with bioluminescence imaging two weeks after primary tumor resection. Immunohistochemical staining showed that the number of TNBC cells in the lymph nodes was significantly reduced in the mice with suppressed PFKFB4, and that metastasis was delayed as a result.

The study also revealed:

• Hypoxia in the TME appears to activate PFKFB4, which in turn activates the expression of integrin β3, a protein that supports the growth and spread of cancer cells. In mouse models genetically modified to inhibit PFKFB4, hypoxia had no effect on the expression of integrin β3.
• Activation of PFKFB4 by the hypoxic TME increases levels of glutathione, an antioxidant manufactured inside the cell that can cause resistance to chemotherapy, effectively protecting several types of cancer cells, including those originating in the breast, colon, lung, larynx and bone marrow.
• Immumohistochemical analysis of tumors from breast cancer patients revealed that in certain breast tumors, PFKFB4 is localized to the nucleus of cancer cells, enabling them to further adapt genetically and metabolically. Elevated PFKFB4 in the nuclei was closely linked to poor survival.

Dr. Dasgupta said he hopes that “information gleaned from this study will provide us with the basis for further research to determine whether PFKFB4 can be suppressed pharmacologically to reduce the risk of recurrence and metastasis in patients with TNBC.”

Co-authors of the study represented Roswell Park Comprehensive Cancer Center and the University of Pittsburgh School of Medicine. The study was funded by the National Institutes of Health Director’s New Innovator Award (DP2), the National Cancer Institute (RO1), the Susan G. Komen Career Catalyst Award, a Roswell Park Alliance Foundation grant to Dr. Dasgupta and a Breast Cancer Coalition of Rochester Predoctoral Fellowship to Tao Dai.

###

Roswell Park Comprehensive Cancer Center is a community united by the drive to eliminate cancer’s grip on humanity by unlocking its secrets through personalized approaches and unleashing the healing power of hope. Founded by Dr. Roswell Park in 1898, it is the only National Cancer Institute-designated comprehensive cancer center in Upstate New York. Learn more at www.roswellpark.org, or contact us at 1-800-ROSWELL (1-800-767-9355) or ASKRoswell@RoswellPark.org.