Grant: Operating Grant

For cancer cells to grow and make metastasis they have to degrade the surrounding tissues, a process that is influence by a particular microenvironment of the tumor that is the lack of oxygen which triggers acidosis. Growing evidence connects newly identified cancer cell structures, invadopodia, to metastasis. Invadopodia concentrates the enzymes involved in tissue breakdown and cell invasion. Despite the crucial importance of invadopodia in tumor spread, few are known about the mechanisms involved in their formation. We have demonstrated that hypoxia is a strong inducer of invadopodia formation and cell invasion in cancer cells. In this project, we are searching for the specific mechanisms involved in invadopodia formation and cell invasion trigger by the tumor microenvironment (lack of oxygen and acidosis). We will test the possibility that hypoxia influences the pH of tumor cells and its microenvironment through molecular modifications of an exchanger involved in cellular pH homeostasis. As a consequence, we will test the hypothesis that enhanced functions of pH-sensitive proteins involved in tumorigenesis is one of the mechanism by which hypoxia promotes invadopodia formation and tumor invasion. This will be assessed using different molecular biology tools as well as unique methods to investigate invadopodia formation and functions in live cancer cells. We also propose to use in vivo metastasis assays in mice and tissue samples from normal patients and highly invasive breast cancer patients to relate our basic studies to metastatic disease. The spread of cancer cells to distal sites of the body is the major cause of cancer patient death. The identification of new mechanisms involved in invadopodia formation and function will be important for developing new markers of disease progression as well as new strategies to interfere with this life-threatening disease.