The Felding Laboratory

Research

Mechanisms and inhibition of tumor metastasis

Our goal is to define and target molecular mechanisms that control tumor metastasis. Metastasis is the main cause of death in cancer patients. If dissemination of tumor cells from primary to distant sites could be prevented or blocked after it has occurred, the mortality of patients with solid tumors could be drastically reduced, and cancer would be curable disease.  To develop effective approaches for prevention and inhibition of metastatic disease, we address four major questions:

1. Which cells are responsible for metastatic dissemination?
2. Which are key genes and functional properties that promote tumor metastasis?
3. How can we target metastatic tumor cells and inhibit functions that are essential for cancer spreading?
4. How do tumor cell metabolism and the host microenvironment control cancer development and dissemination?

We hypothesize that genetic alterations and aberrant tumor cell metabolism determine metastatic activity and cancer progression.  Focusing primarily on breast cancer, we found that a subset of aggressive cancer cells within a primary tumor express constitutively activated adhesion receptors that promote tumor cell dissemination. These activated adhesion receptors can serve as targets for identification and inhibition of metastatic tumor cells. Following one of the most deadly forms of breast cancer metastasis, we found that brain metastatic breast cancer cells adapt to the microenvironment of the brain by metabolic alterations that foster growth within the brain tissue. Dissecting the earliest steps of breast cancer colonization of the brain, we were able to define sequential events that are critical for tumor cell survival and penetration of the blood brain barrier. These mechanisms involve adhesive functions, interaction with vascular cells, and coagulation activity that could be targeted for prevention of brain metastatic disease.

Following the challenge to develop break-though ideas that could lead to tangible reduction in breast cancer mortality, we focused on tumor cell metabolism and demonstrated that mitochondrial complex I activity controls aggressiveness in breast cancer. Our finding show that regulation of the tumor cell NAD+/NADH redox balance through complex I affects breast cancer growth and metastasis. The results translated into a new therapeutic approach based on treatment with NAD⁺ precursors that prevent breast cancer progression. Current standard of care for cancer patients relies primarily on chemo- and radiation therapies aimed at killing the tumor cells. However, evolutionary models predict, and clinical experience indicates, that selective pressure imposed by these approaches causes survival of resistant clones that eventually reactivate the disease. Therapeutic normalization of tumor cell metabolism could be an effective way to interfere with the expansion of residual clones. Thus, combination of standard therapy with the treatment we developed may halt breast cancer progression and prevent recurrence.

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