Metabolic Mechanisms in Cancer Progression Most cells in the body depend on direct contact with their surroundings for survival. This protective mechanism is inactivated in blood cells and during tissue remodeling. Anchorage- dependence is lost in cancer cells while they spread throughout the body (metastasis), and may lead to the patient's death. We have identified a set of related molecules, one of which activates a new signaling pathway within non-adherent cells. We will investigate the mechanisms of action of this molecule with the goal to identify drug targets for future anti-metastasis therapy.
Metabolic Mechanisms in Cancer Progression Most cells in the body require the physical interaction with their microenvironment for survival. Once they lose contact to the surrounding cells and stroma they die via anoikis. The ability to survive and expand deadherently is physiologically limited to hematopoietic cells and to phases of tissue remodeling after damage. Pathologically, this process is activated in cancer cells, when they are shed from their primary tumors - the step that initiates metastasis. Despite the importance in pathophysiology, the molecular mechanisms underlying anchorage-independence are incompletely understood. The ligation of adhesion receptors on cells after their release from the substratum may convey an anti-apoptosis signal. While metabolic changes that allow the affected cells to produce energy for function and proliferation are also required, they have not been elucidated. Osteopontin is a metastasis gene associated with multiple malignancies, including breast cancer. We have identified a splice variant of this cytokine, called Osteopontin-c, which supports the anchorage-independent expansion of cancer cells via peroxide signaling. Remarkably, further investigation indicated that Osteopontin-c affects the cellular energy homeostasis in a manner that depends on peroxide intermediates and leads to enhanced ATP generation. We have found that unspliced Osteopontin-a increases the glucose levels in deadherent breast tumor cells, which may provide the biochemical fuel for Osteopontin-c dependent energy production. Based on our published and preliminary results, we hypothesize that Osteopontin-c promotes anchorage-independent growth in breast cancer, thus enabling the formation of metastases. It accomplishes this - via peroxide signaling - by skewing the cell metabolism toward enhanced ATP generation, which counteracts the energy deficit caused by loss of attachment. Synergy with the full-length form Osteopontin-a enhances the effect. Specific Aim 1: Elucidate the contributions by peroxides to Osteopontin-c induced anchorage- independence. Specific Aim 2: Define the peroxide-dependent signaling pathways induced by Osteopontin-c. Specific Aim 3: Characterize amplification of Osteopontin-c signaling by Osteopontin-a in deadherence. Our project is significant because the mechanistic explanation of Osteopontin actions on circulating cells will define potential drug targets for patients with aggressive cancers. The work is also of significance for strengthening the education and research environment in cancer at the College of Pharmacy, University of Cincinnati.
