Grant: Project Grant

Caveolin-1 (CAV1) expression is associated with poor outcomes in aggressive breast and prostate cancer. CAV1 is found in caveolae, small invaginations in the plasma membrane of cells and also in flat domains called scaffolds. Understanding the contribution of CAV1 to cancer malignancy requires defining its role in these two domains. However, caveolae and scaffolds are both smaller than the diffraction limit of light, making them difficult to visualize by standard microscopy. We have developed super-resolution microscopy and artificial intelligence-based computational approaches to study this protein in each of these membrane domains and will now apply them to study CAV1 function in tumor progression and more particularly in tumor cell metabolism. Cancer cells switch their metabolism from mitochondrial respiration, that generates high energy for each molecule of glucose consumed by the cell, to a fermentation like process that does not produce high energy levels but does produce the building blocks (sugars, nucleic acids, amino acids, fats) required to build the cellular macromolecules (proteins, DNA, membranes) that are necessary for cell growth and division. A critical protein that promotes the metabolic switch of cancer cells is pyruvate kinase M2 (PKM2), whose expression in place of the more ubiquitously expressed PKM1, slows metabolic supply to mitochondria. We have found that CAV1 interacts with PKM2 and will now study which CAV1 domain (caveolae or scaffolds) interacts with PKM2. We will test how CAV1 regulates tumor cell metabolism and impacts tumor cell survival and migration and assess whether available clinical inhibitors of metabolism may be useful for the treatment of aggressive CAV1-positive cancers. This work will advance our understanding of highly aggressive breast and prostate cancers and will help us identify new mechanisms and molecules that can be targeted to treat these cancers.