Final Report Summary - TUMETABO (Glycolytic contribution to cancer growth and metastasis)
Hypoxia is a cancer hallmark that imposes a selection pressure on tumor cells. It promotes (i) the uncoupling between glycolysis and oxidative phosphorylation together with an increased glycolytic flux in order to optimize oxygen-independent energy production and cell proliferation (the glycolytic phenotype), (ii) the emergence of tumor cells able to directly or indirectly stimulate the formation of new blood vessels from pre-existing ones (the angiogenic phenotype), and (iii) tumor cell dissemination (the metastatic phenotype). While these adaptations are usually studied independently of each other, we considered the necessity of coordination between them during tumor development. Our general hypothesis was that the glycolytic switch would precede and favor angiogenesis and tumor metastasis. During ERC Starting Grant 243188 TUMETABO, we identified that lactate, the end-product of a glycolytic metabolism, triggers angiogenesis in cancer and other pathologies, and stimulates cancer cell migration. We further identified that several types of mitochondrial dysfunctions promote cancer metastasis as long as they are associated with the production of reactive oxygen species (mtROS) within a sublethal dose range. For anticancer therapy, molecular characterization of these processes grounded the production and validation of new inhibitors of inward lactate transporter MCT1. These drugs can simultaneously exert antimetabolic, anti-angiogenic and antimigratory effects in cancer. Specific inactivators of mtROS production were found to prevent metastatic dissemination from a primary human breast cancer in mice. New modalities were also developed for cancer imaging. For wound healing therapy, we validated FDA-approved PLGA as a lactate-releasing polymer that accelerates the healing of ischemic injuries and excisional skin wounds in preclinical assays. Together, this work identified new concrete strategies and experimental drugs for the clinical management of cancer and other diseases.